arturo san feliciano · cardiac insufficiency pre charge post- charge compensating mechanisms ......
TRANSCRIPT
![Page 1: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/1.jpg)
3. Pharmacophore Identification in
Natural Cardenolides
Identificación del Farmacóforo en Cardenolidas Naturales
Arturo San Feliciano
Department of Pharmaceutical Chemistry Faculty of Pharmacy, CIETUS, IBSAL.
University of Salamanca. Salamanca. Spain
![Page 2: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/2.jpg)
1 - Antecedents
2 - Design and Synthesis of
Cardenolide Analogues
3 - Bioevaluation
4 - Discussion and conclusions
Contents
![Page 3: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/3.jpg)
TYPES
· Acute
· Chronic
· Right
· Left
· Sistolic
· Diastolic
· Congestive
CONTRACTION
VOLUME
EJECTED
VOLUME
MINUTE
FRECUENCY
CARDIAC INSUFFICIENCY
POST-CHARGE PRE-CHARGE
COMPENSATING MECHANISMS
· Miocardic hypertrophia
· hydrosaline retention
· Neurohormonal activation
![Page 4: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/4.jpg)
· DIURETICS · VASODILATORS · POSITIVE INOTROPICS
· b- BLOCKERS · OTHER
TREATMENT OF CARDIAC INSUFFICIENCY
![Page 5: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/5.jpg)
· DIURETICS · VASODILATORS · POSITIVE INOTROPICS increase intracelular cAMP
Increase intracelular Ca 2+
Modulate ionic pumps / channels
Multiple mechanism · b- BLOCKERS
· OTHER
TREATMENT OF CARDIAC INSUFFICIENCY
![Page 6: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/6.jpg)
· DIURETICS · VASODILATORS · POSITIVE INOTROPICS increase intracelular cAMP
b1-Agonists
Phosphodiesterase Inhibitors Increase intracelular Ca 2+
Increase Ca 2+ liberation
Sensitisers to Ca 2+ action
Modulate ionic pumps / channels
Digitalis and related Glycosides
Multiple mechanism · b- BLOCKERS
· OTHER
TREATMENT OF CARDIAC INSUFFICIENCY
![Page 7: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/7.jpg)
ESTRUCTURA DE LA ATPasa-Na+,K+
![Page 8: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/8.jpg)
ACTIVIDAD TRANSPORTADORA DE LA ATPasa-Na+,K+
E 1
E 1 P ( 3 N a + ) E 2 ( 2 K
+ )
E 2 P
3 N a +
A T P
A D P
3 N a +
2 K +
P i
2 K +
o u a b a í n a
E x t e r i o r
C i t o p l a s m a c e l u l a r
![Page 9: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/9.jpg)
EFFECTS AND TROUBLES
OF DIGITALIS CARDIOTONICS
PHYSIOLOGIC Positive Inotropism ( POTENCY + )
Negative Chronotropism ( RATE - ) TOXIC / ADVERSE
![Page 10: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/10.jpg)
PHYSIOLOGIC Positive Inotropism ( POTENCY + )
Insufficiency Negative Chronotropism ( RATE - )
Tachycardia, atrial fibrilation TOXIC / ADVERSE
EFFECTS AND TROUBLES
OF DIGITALIS CARDIOTONICS
![Page 11: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/11.jpg)
PHYSIOLOGIC Positive Inotropism ( POTENCY + )
Insufficiency Negative Chronotropism ( RATE - )
Tachycardia, atrial fibrilation TOXIC / ADVERSE Low Therapeutic Index Hipokalemia Bradicardia Ventricular extrasistolia Digitalisation (accumulation) Death … Nausea, vomiting, diarrhoea
EFFECTS AND TROUBLES
OF DIGITALIS CARDIOTONICS
![Page 12: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/12.jpg)
PHYTOCHEMICAL ANTECEDENTS Studies on Digitalis sp. endemic to the West of Spain Studies on native Spanish Conifers (Juniperus)
![Page 13: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/13.jpg)
Digitalis thapsi
(Scrophulariaceae)
O O
OH
gli-O
CARDENOLIDES
DIGITANOLS
OTHER
Phytochemical studies at the USAL:
digitoxin
![Page 14: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/14.jpg)
O
O O O
O
O
HO OH
HO
HO
O
O
OH
Molecules 5, 51- 81 (2000)
( b -D-DIG) 3 - O
O O
OH
OH
DIGOXIN
OH
![Page 15: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/15.jpg)
COMMUNIC ACIDS ,
PIMARIC ACIDS,
OTHER TERPENOIDS
LIGNANS
Junipers Juniperus
(sect. Oxycedrus)
Sabines Juniperus phoenicea
( sect. sabina ) HOOC
Sandaracopimaric acid
Phytochemical studies at the USAL:
![Page 16: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/16.jpg)
HOOC
Sandaracopimaric Acid
O O
OH
( b -D-DIG) 3 - O
DIGITOXIN
DIGITALIS - LIKE
CARDIOTONICS
?
OBJECTIVE
![Page 17: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/17.jpg)
1 - Antecedents
2 - Design and Synthesis of
Cardenolide Analogues
3 - Bioevaluation
4 - Discussion and conclusions
Contents
![Page 18: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/18.jpg)
Natural and Natural-Product Related Cardiotonics: Cardenolides
O
OH
(b-D-DIG) 3-O
O
DIGOXIN
OH
O
OH
-L-RHAMN-O
O
HO
HO
HO
OUABAIN
O
OOO
O
O
HOOH
HO
HO
O
O
OH
OH
DIGOXIN
![Page 19: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/19.jpg)
OH
H
O
O
O
OO
OHOH
H
H
GOMPHOSIDE
UZARIGENIN
Natural and Natural-Product Related Cardiotonics: Cardenolides
![Page 20: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/20.jpg)
R1
OH
R2
O
IC50 (nM)
-COCH2OH
-CH2OH
-CH2NH2.HCl
-CH2NO2
-CH2CH2NO2
-CH2NH2·HCl
-CH2NO2
1070
360
99
12
45
270
88
R1
R2
-L-rhamnose
-L-rhamnose
-L-rhamnose
-L-rhamnose
-L-rhamnose
b-D-digitoxose
b-D-digitoxose
O
N
NH
NH2
NH
Natural and Natural-Product Related Cardiotonics: Cardenolides
![Page 21: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/21.jpg)
OH
MeOOC
ONH
ERYTHROPHLEINE
O
Natural and Natural-Product Related Cardiotonics: Terpenoidal alkaloids
![Page 22: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/22.jpg)
Main Objectives
1. Synthesis of diterpenic analogues of
cardenolides, using natural pimarane
derivatives as starting materials.
2. Search for the minimum structural
requirements for cardiotonic activity.
3. Total synthesis of simpler inotropic
substances.
![Page 23: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/23.jpg)
PIMARANES
natural CYCLOHEXANES
synthesis
INDANES
synthesis
OO
OH
OO
OHR
1
R2
OO
Z
OH
OO
OHX
Z
Y
H
Objectives
![Page 24: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/24.jpg)
Cardenolide Analogues
Pimaranes
digitoxigenin Cyclohexanes
Indanes
Dinor-seco-steroids
D
D
B
A,B A,B
D C
B A
![Page 25: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/25.jpg)
The Pimarane Strategy
OH
O O
Gly-O
C D
glycoside
B A
steroidal A-D rings
![Page 26: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/26.jpg)
The Pimarane Strategy
glycoside
OH
O O
Gly-O
C D
B A
steroidal A-D rings
O
OO
Z
A B
C
OH
glucose (sugar) solubilizer
A - C rings, 5-H
lack of Ring D
![Page 27: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/27.jpg)
The Cyclohexane Strategy
OH
OO
Gly-O
C D
steroidal A-D rings
glycoside
A B
butenolide
![Page 28: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/28.jpg)
The Cyclohexane Strategy
OO
OHY
Z
C
espacer solubilizer lack of Rings
A-B and D
OH
OO
Gly-O
C D
steroidal A-D rings
glycoside
A B
butenolide
![Page 29: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/29.jpg)
The Indanol strategy
OH
C D
OO
Gly-O
butenolide
Cardenolide C-D rings
A-B rings and glycoside
![Page 30: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/30.jpg)
The Indanol strategy
OH
C D
OO
Gly-O
butenolide
Cardenolide C-D rings
A-B rings and glycoside
Y OH
R
X
D C
Butenolide or equivalent
Cardenolide C-D rings
Z
spacer (Y) and solubilizer (Z) fragments
![Page 31: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/31.jpg)
Butenolide or
equivalent
CD + A rings
X,Y = C, N
Z Solubilizer Lack of ring B
X
OHX
YZ
The di-nor-seco-steroid strategy
![Page 32: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/32.jpg)
The Pimarane-butenolide Synthesis.
OO
Z
OH
HOOC
FROM Juniperus phoenicea or Tetraclinis articulata
![Page 33: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/33.jpg)
The Pimarane-butenolide Synthesis.
1. The side Chain
OO
Z
OH
R = H, Ac
HOOC
FROM Juniperus phoenicea or Tetraclinis articulata
R1
R1
OR
BBN, H2O2
![Page 34: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/34.jpg)
The Pimarane-butenolide Synthesis.
2. The 14-hydroxyl function
R1
OR
BH3-THF
OR
OH
H
![Page 35: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/35.jpg)
R1
OR
BH3-THF
OR
OH
H
The Pimarane-butenolide Synthesis.
2. The 14-hydroxyl function
OR
OH
H
![Page 36: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/36.jpg)
The Pimarane-butenolide Synthesis.
2. The 14-hydroxyl function
R1
OR
BH3-THF
OR
OH
H
R = H, Ac, THP, TBDMS, TBDPS
OR
OH
H
![Page 37: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/37.jpg)
The Pimarane-butenolide Synthesis.
2. The 14-hydroxyl function
R1
OR
BH3-THF
OR
OH
H
R = H, Ac, THP, TBDMS, TBDPS
R
O
Si No association O - B
face protected
OR
OH
H
![Page 38: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/38.jpg)
The Pimarane-butenolide Synthesis.
3. The Butenolide
OH
OAc
H
OAc
H
OAcO
Jones; SOCl 2; CH2N2
HCl; NaOAc/Ac2O
![Page 39: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/39.jpg)
The Pimarane-butenolide Synthesis.
3. The Butenolide
OH
OAc
H
OAc
H
OAcO
Jones; SOCl 2; CH2N2
HCl; NaOAc/Ac2O
OH
H
O
OH
H
OOO
OH
+
Reformatsky
![Page 40: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/40.jpg)
The Pimarane-butenolide Synthesis.
3. The Butenolide
OO
R1
OH
OH
OAc
H
OAc
H
OAcO
Jones; SOCl 2; CH2N2
HCl; NaOAc/Ac2O
OH
H
O
OH
H
OOO
OH
+
Reformatsky
![Page 41: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/41.jpg)
The Pimarane-Butenolide Synthesis.
4. The End Products
R = COOH, CH 2 OH, O
O HO
HO
OH
OH
O O
R 1
OH
O O
R
OH
![Page 42: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/42.jpg)
The Synthesis of
Cyclohexylmethylbutenolides R
1
OO
OHR
2
R1= H, Me
R2= H, Me
OCOOH
O Cl4 steps
Mn(OAc)3
HOAc, KOAc
a:(COCl) 2/Benz
b:CH2N2; HCl
Horner
![Page 43: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/43.jpg)
The Synthesis of
Cyclohexylmethylbutenolides R
1
OO
OHR
2
R1= H, Me
R2= H, Me
OO
OH
OCOOH
O Cl
OO
OO
4 steps
OH
Mn(OAc)3
Br
HOAc, KOAc
a:(COCl) 2/Benz
b:CH2N2; HCl
Horner
NBS,HClO 4 n-Bu3Sn +
![Page 44: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/44.jpg)
The Enantioselective Synthesis of Indanols
RR
OO O
O O
O
(R = H, Me)
![Page 45: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/45.jpg)
The Enantioselective Synthesis of Indanols
OH
RR
OO O
O O
O
R
O
O
OOH
(R = H, Me)
(R = H) (R = Me)
S-(-)-proline
piperidine, DMFO
O O
O
Tetrahedron Asymm. 8, 2075 (1997)
HAJOS-PARRISH ketones ( ee 95-100% )
![Page 46: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/46.jpg)
The Indanol Synthesis: C-1-elongation
OH
O
O
OH
O
OH
O
S
SOH
HS(CH 2)3SH
BF3.Et2O
PH 3P=CH 2 HgO, THF/H 2O
BF3.Et2O
I
![Page 47: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/47.jpg)
The Indanol Synthesis: C-1-elongation
OH
O
O
OH
O
OH
O
O
O
S
SOH
BF3.Et2O
O
O
PH 3P=CH 2S
S
HS(CH 2)3SH
HS(CH 2)3SH
BF3.Et2O
PH 3P=CH 2
p-TsOH
HgO, THF/H 2O
HgO, THF/H 2O
BF3.Et2O
HS(CH 2)3SH TMSCl
BF3.Et2O
![Page 48: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/48.jpg)
The Indanol Synthesis: C-1-elongation
OH OH OH OH
CHO
OH
CHOOH OH
CHO CHOOH OH
I
BH3.THF
H2O2
PCC
PCC
1:1
1:1
BH3.THF
H2O2
II
III
![Page 49: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/49.jpg)
The Indanol Synthesis: C-1-elongation
OH OH OH OH
CHO
OH
CHO
I
OH OH
BH3.THF
H2O2
CHO CHOOH OH
BH3.THF
H2O2
II
PCC
PCC
1:1
1:1
OH
CHO
OH
COOMe
Ph 3P=CHCOOMe
III
III OH
COOMe
O
deprotection
![Page 50: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/50.jpg)
The Indanol Synthesis: Stereochemical Control
OH
CHO
OH
CHO
Y Y
X X
?
![Page 51: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/51.jpg)
The Indanol Synthesis: Stereochemical Control
X,Y H =O H, OH OH, H -O-(CH2)2-O- -O-(CH2)3-O- -S(CH2)3S-
DH b -0.02 +0.12 -1.64 +1.39 -1.09 -0.85 -2.98
(Kcal/mole)
OH
CHO
OH
CHO
Y Y
X X
?
![Page 52: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/52.jpg)
The Indanol Synthesis: Stereochemical Control
OH
CHO
OH
CHO
S
S
S
S
5% KOH / MeOH
b = 1 / 9
OH
CHO
OH
CHO
Y Y
X X
?
X,Y H =O H, OH OH, H -O-(CH2)2-O- -O-(CH2)3-O- -S(CH2)3S-
DH b -0.02 +0.12 -1.64 +1.39 -1.09 -0.85 -2.98
(Kcal/mole)
![Page 53: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/53.jpg)
The Indanol Synthesis: Final Products
R
H, Me
X,Y
H,H; =O; H,OH;
H,OAc;
-O-(CH2)2-O-; -O-(CH2)3-O-;
-S-(CH2)3-S-; =N-N=C(NH2)2
Z
COMe; COOMe; SMe, NO2
G H,OH; CHNO2;
N-N=C(NH2)2
OH
Z
Y
Z
Y
XX
R R
OHY
X
R
Y
X
R
G G
![Page 54: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/54.jpg)
The Synthesis of Ent-Indanols
O
O
O
+
O
O
N
N
NNH2N
NH2
NH2
NH2
30
R-(+)-proline
43
![Page 55: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/55.jpg)
OTMS
O
O
OTMS
O
H2N
OTMS
O
N
NC
OTMS
O
HO
OTMS
O
NOH
O
O
5
6a
7a
8a
9a1
a
b
c
a) TMSTf, Et3N, CH2Cl2
b) NH4OAc, NaBH3CN, MeOH
c) Piperidine, HCl/MeOH, NaBH3CN (r.t.)
OO
OHX
Z
Y
H
Synthesis of B,B-dinor-B-seco-steroids
![Page 56: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/56.jpg)
a) TMSTf, Et3N, CH2Cl2
c) Piperidine, HCl/MeOH, NaBH3CN (r.t.)
OO
OHX
Z
Y
H
Synthesis of B,B-dinor-B-seco-steroids
OH
O
OOTMS
O
1 11
ca
+
OTMSN
NC
OTMSN
N
NCN
12a 13a
13b12b
![Page 57: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/57.jpg)
+
OH
O
O
OH
O
NC
CNOH
O
NC
CNOH
O
NC
CN
+
OH
O
NO2
OH
O
NO2
OH
O
OH
O
OH
O
NCOH
O
NC
1
14 15a 15b
16a 16b 17a 17b
18a 18b
+
+
a
b
c d
e
OO
OHX
Z
Y
H
a) malononitrile, b-alanine,
HOAc / EtOH, r.t.
b) DIBAL-H 1M, hex, THF, 0ºC
c) MeNO2, EDA, D
d) H2, Pd/C (10%), EtOH, r.t.
e) TosMIC, KOtBu, EtOH,
1,2-dimethoxyethane, r.t.
Synthesis of B,B-dinor-B-seco-steroids
![Page 58: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/58.jpg)
OH
O
O
OH
O
COOEt
OH
O
EtOOC
OH
O
COOEt
OH
O
COOEt
OH
O
COOEt
OH
O
COOEt
1
19
20
21a
21b
22a
22b
a b c
a) Ph3P=CHCOOEt, benz., D
b) H2, Pd/C (10%), EtOH, r.t.
c) I) LDA, HMPTA, THF, -78ºC,
ii) H2C=NMe2I, THF, - 42ºC to r.t.
iii) MeI, dioxane, 90ºC, iv) NaHCO3, H2O/EtOAc, r.t.
OO
OHX
Z
Y
H
Synthesis of B,B-dinor-B-seco-steroids
![Page 59: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/59.jpg)
b) i) Me3SiOC(=CH2)CH=CHOMe, benz.
ii) HCl (c), CHCl3, r.t
c) H2, Pd/C (10%), EtOH, r.t.
OO
OHX
Z
Y
H
Synthesis of B,B-dinor-B-seco-steroids
OH
O
COOEt
OH
O
COOEt
EtOOC
O
EtOOC
O
EtOOC
EtO
OEt22a,22b
23 24 27
+
b
c
EtOOC
O
EtOOC
O
EtOOC
EtO
OEt25 26 28
+ c
![Page 60: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/60.jpg)
OO
OHX
Z
Y
H
Synthesis of B,B-dinor-B-seco-steroids
a) LAH, Et2O, r.t.
b) TBDMSTf, Et3N, CH2Cl2
EtOOC
EtO
OEt
EtO
OEt
OH
OH
HO
EtO
OEt
OH
OH
TBDMSO
2732 35
a b
![Page 61: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/61.jpg)
EtO
OEt
OH
OH
TBDMSO
EtO
OEt
OH
O
TBDMSO
EtO
OEt
OH
OH
TBDMSO
OH
O
TBDMSO
O
OH
O
TBDMSO
HO
OH
TBDMSO
O
HO
33 36
3537
38
39
+
a
ab
OO
OHX
Z
Y
H
Synthesis of B,B-dinor-B-seco-steroids
a) PCC, Py, CH2Cl2,
b) NaBH4, MeOH, -15ºC
![Page 62: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/62.jpg)
1 - Antecedents
2 - Design and Synthesis of
Cardenolide Analogues
3 - Bioevaluation
4 - Discussion and conclusions
Contents
![Page 63: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/63.jpg)
Bioevaluation Methods:
Spontaneously bating right atria (rat)
Electrically stimulated left atria (rat)
![Page 64: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/64.jpg)
Bioevaluation Methods:
Spontaneously bating right atria (rat)
contraction and rate
Electrically stimulated left atria (rat)
contraction
![Page 65: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/65.jpg)
Bioevaluation Methods:
Spontaneously bating right atria (rat)
contraction and rate
Electrically stimulated left atria (rat)
contraction
Na,K – ATPase (rat)
Na,K - ATPase isozymes (human)
![Page 66: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/66.jpg)
Bioevaluation results:
Cyclohexanebutenolides:
inactive Pimaranebutenolides: inactive // negative inotropic
Indanederivatives:
positive inotropic
Dinorsecosteroids: pending
![Page 67: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/67.jpg)
-50
0
50
100
150
200
250
300
% O
F C
ON
TR
OL
-8 -7 -6 -5 -4 -3
Concentration (Log M)
36b
17a
17b
CONTRACTION FORCE
RIGHT ATRIA
The Indanol Evaluation
![Page 68: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/68.jpg)
-50
0
50
100
150
200 %
OF
CO
NT
RO
L
-8 -7 -6 -5 -4 -3
Concentration (Log M)
36b
Digoxin
CONTRACTION FORCE
LEFT ATRIA
The Indanol Evaluation
![Page 69: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/69.jpg)
Indane Positive Inotropics
NO 2
N
N H 2 N
NH 2
N
N
N H 2 N
NH 2
N
NH 2
NH 2
36b
20
![Page 70: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/70.jpg)
The Indanol Evaluation Rat Na+,K+ - ATPase inhibition
[20 ]/ M ; [ouabain] / M
50
10 -8 10 -7 10 -6 10 -5 0
100
130
resi
du
al N
KA
act
ivit
y /
%
J. Med. Chem. 45, 127 (2002)
![Page 71: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/71.jpg)
IC50 (M)
Compound 20 Ouabain
2.10-6 3.10-7
5.10-4 5.10-5
The Indanol Evaluation Rat Na+,K+ - ATPase inhibition
![Page 72: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/72.jpg)
Human Na,K-ATPase isoenzymes activities
in absence (0) or presence of 36b
0
50
100
150
200
250
0 a
1b
1
1m
M a
1b
1
0a1
b1
1m
Ma1
b1
0a2
b1
1m
M a
2b
1
0a2
b1
1m
M a
2b
1
0 a
2b
1
5m
M a
2b
1
5m
M a
2b
1
0a3
b1
1m
M a
3b
1
0a3
b1
1m
Ma3
b1
Data #CAR 10 pmol
0
1b
1
0
1b
1
1m
M
1b
1
1m
M
1b
1
1m
M
b
1
1m
M
b
1
5m
M
b
1
5m
M
b
1
1m
M
b
1
1m
M
b
1
0
b
1
0
b
1
0
b
1
0
b
1
0
b
1
1b1
2b1
3b1
![Page 73: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/73.jpg)
1 - Antecedents
2 - Design and Synthesis of
Cardenolide Analogues
3 - Bioevaluation
4 - Discussion and conclusions
Contents
![Page 74: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/74.jpg)
The reason for the inactivity of pimarane-lactones The Reason for the Inactivity of Pimarane-butenolides?
![Page 75: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/75.jpg)
The Reason for the Inactivity of pimarane-butenolides?
![Page 76: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/76.jpg)
The Reason for the Inactivity of pimarane-butenolides?
D H = 14 kJ / mole
![Page 77: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/77.jpg)
The Reason for the Activity of Guanylhydrazones?
superimposition guanylhydrazone / digitoxigenin
*
![Page 78: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/78.jpg)
The Reason for the Activity of Guanylhydrazones?
superimposition guanylhydrazone / digitoxigenin
*
![Page 79: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/79.jpg)
The Reason for the Activity of Guanylhydrazones?
superimposition guanylhydrazone/erythrophleine
*
![Page 80: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/80.jpg)
The Reason for the Activity of Guanylhydrazones?
superimposition guanylhydrazone/erythrophleine
*
![Page 81: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/81.jpg)
The Reason for the Activity of Guanylhydrazones?
superimposition guanylhydrazone/erythrophleine
*
![Page 82: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/82.jpg)
The Reason for the Activity of Guanylhydrazones?
superimposition guanylhydrazone/erythrophleine
*
*
![Page 83: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/83.jpg)
The Reason for the Activity of Guanylhydrazones?
superimposition guanylhydrazone/erythrophleine
*
*
![Page 84: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/84.jpg)
The Ent-Indanol Evaluation
- 100
- 50
0
50
100
150
200
250
1,E - 09 1,E - 07 1,E - 05 1,E - 03
Concentration (M)
Inotr
op
ic R
esp
on
se
(% o
f C
on
tro
l)
11
15
16
19
20
22
- 100
- 50
0
50
100
150
200
250
1,E - 09 1,E - 07 1,E - 05 1,E - 03
Concentration (M)
Inotr
op
ic R
esp
on
se
(% o
f C
on
tro
l)
11
15
16
19
20
22
11 11
15 15
16 16
19 19
20 20
22 22
43
CONTRACTION FORCE
RIGHT ATRIA
![Page 85: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/85.jpg)
The Ent-Indanol Evaluation
Inotropic activity of guanylhydrazones (left atria)
and effect on the cardiac frequency (right atria)
compound Emax(1) Emax(2) Emax(3)
22 (norm) 129 6.5 33.7±6.3 0.3
43 (ent) 170 66.5 - 5.1±7.4 0.3
Digoxin 103 14.3 - 28.3±3.7 10-3
Ouabain 122 58.4 80.4±39.4 10-3
(1) % of basal force, (2) % of basal frequency, (3) mM
![Page 86: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/86.jpg)
superimposition of bishydrazone enantiomers?
N
N
NNH2N
NH2
NH2
NH2N
N
NNH2N
NH2
NH2
NH2
n e
* *
* *
![Page 87: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/87.jpg)
superimposition of the enantiomers?
n e
* *
*
*
![Page 88: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/88.jpg)
superimposition of the enantiomers
n e
* *
![Page 89: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/89.jpg)
superimposition of the enantiomers
n e
*
*
n e
* *
![Page 90: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/90.jpg)
superimposition of the enantiomers?
n e
* *
![Page 91: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/91.jpg)
2b1 isoenzyme activity in absence (0) or
presence of 36b (n), 43 (ent) and ouabain
0
1000
2000
3000
4000
5000
6000
dp
m/o
oci
to
0 a
2b
1
33
a2
b1
43
a2
b1
Ou
abaí
na
a2b
1
n.i
.
0
b
1
33
b1
43
b1
Ou
ab
.
b
1
0 n
.i.
enantio (43)
normal (36b)
ouabain
(0)
![Page 92: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/92.jpg)
Rb
Uptake
(%)
100
Column 1
compound 36b normal 43 enantio
3b11b1 2b1
50
86
isozyme b b 1 3 11 1 2b
The Ent-Indanol Evaluation
![Page 93: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/93.jpg)
Conclusions: - We have developed a synthetic methodology
for the preparation of a variety of cardioactive
hydroindene derivatives.
- Those belonging to the normal steroidal
series, act through inhibition of Na,K-ATPase
- Those belonging to the enantio series, being
more potent, does not act by this mechanism
- They constitute ones of the simplest
homocyclic structures reported as
cardiotonics and negative inotropics.
![Page 94: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/94.jpg)
Chemistry QF-USAL
Dr. Manuel Medarde
Dr. José Luis López
Dr. Fernando Tomé
Dr. Belen Hebrero
Dr. Melchor Boya
Dr. Concepción P. Melero
Dr. Luis G. Sevillano
Pharmacology - USAL
Dr. María José Montero
Dr. Rosalía Carrón
Dr. Pilar Prieto
Molecules 5, 51
Tetrahedron 45, 1815
Tetrahedron Letters 35, 8683
An. Quim 91, 89,
Synt. Commun. 25, 1377
Eur J Med Chem 26, 799
Bioorg Med Chem Lett 8, 3217
Eur J Med Chem 28, 887
Bioorg Med Chem 7, 2991
Tetrahedron 58, 1266
J. Med. Chem. 45, 127
![Page 95: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/95.jpg)
Biochemical Assays
Drs. Lionel G. Lelièvre, Concepción P. Melero
University of Paris 7. France
Drs. Käthi Geering, Gilles Crambert, Luis G. Sevillano
University of Lausanne. Switzerland.
Financing:
DGICYT, CICYT, JCyL, (SPAIN)
![Page 96: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/96.jpg)
Muito obrigado!!
![Page 97: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/97.jpg)
UNIVERSITY OF SALAMANCA
1218
![Page 98: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/98.jpg)
![Page 99: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/99.jpg)
![Page 100: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/100.jpg)
The Reason for the Activity of Guanylhydrazones?
superimposition guanylhydrazone/erythrophleine
Erythrophleine conformers
![Page 101: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/101.jpg)
1 + 2 + 3
Superposición de secoesteroide con digitoxigenina y eritrofleína
1 + 2 2 + 3
Digitoxigenin dinorsecoesteroid erythrophleine 1 2 3
superimposition dinorsteroid, digitoxigenin, erythrophleine
![Page 102: Arturo San Feliciano · CARDIAC INSUFFICIENCY PRE CHARGE POST- CHARGE COMPENSATING MECHANISMS ... Digitalis and related Glycosides Multiple mechanism · b- BLOCKERS · OTHER ... OF](https://reader033.vdocuments.net/reader033/viewer/2022053022/604f6b9f12d18d08861f9a0f/html5/thumbnails/102.jpg)
UNIVERSITY OF SALAMANCA
1218
Universidad 2oo2 Universidad 2oo2