fiorillo saycs 2015
TRANSCRIPT
Novel 13-(di)arylalkyl berberines with
antiproliferative activityGaetano Fiorillo, Franco Buzzetti,
Paolo Lombardi, Tanjia Monir Syeda
via G. Di Vittorio 70, 20026 Novate Milanese, Milano, Italy
Email: [email protected]
Rimini 27-29 October 2015
BerberineBackground History
Bitter-tasting isoquinoline quaternary alkaloid extracted
from plants of the genus Berberis, Coptis and others.
In use in the Ayurvedic and Chinese medicines since hundreds of years.
It shows diverse pharmacological activities:
Anti-microbial/parasitic,
Anti-diarrheal, anti-inflammatory,
Anti-arryhthmic,
Cholesterol-lowering
Anticancer
The precise molecular basis of its many biological
activities are still debated
Modulation of protein expression by interaction with
nucleic acids is postulated
The interactions between berberine and nucleic acids,
reported since 1962, could lead to its anticancer effect
Mazzini, S. et al, Bioorg Med Chem,
2003, 505–514
(NMR Studies)
Ferraroni, M. et al, Chem. Commun.
2011, 4917-4919
(RX studies)
intercalation
minor groove binding
BerberineDNA Interaction
Berberine represents an interesting and
attractive natural lead compound
Chemical modifications might select more
specific medical indications resulting in
derivatives with better (or different)
biological effects compared to the parent
berberine
Performing rational chemical modifications of
berberine structure led to a new class of
derivatives with antitumour properties
Chemical
Programme
Berberin
e
BerberineAnticancer Properties
Since aromatic interactions are ubiquitous in nature, and their geometry is relevant for the molecular recognition in biological system, that could result in better (or different)
biological effects with respect to the parent Berberine
Chemical
Programme
from very low to low yields - better with activated halides or iodides - berberine back from loss of acetone major by-product
Alkylation of enamine (7,8-dihydroberberine)
Berberine derivativesSynthetic Methods
from low to moderate yields -berberine and tetrahydroberberinefrom disproportionation of enamineas major by-products
generally from good to very good yields
Uncommon aldehyde-enamine condensation1,2
2 Iwasa, K, et al., Planta Medica, 1997, 196 1 Cook, AG, Enamines Synthesis, Structure and reaction, 1988, pag 200-201
Berberine derivativesSynthetic Methods
1) Commercially available aldehydes
2) Commercially available alcohol followed by oxidation
(PCC or TEMPO)
3) Homologation starting from aldehydes 1) & 2)
Of course, most of starting materials, reagents, solvents,
and disposables are from
Berberine DerivativesAldehyde Intermediates
Another route was used
Berberine DerivativesAldehyde Intermediates
Berberine
DerivativesBinding to DNA
1.770.35
2.11
11.01
7.6 7.586.8
0
2
4
6
8
10
12
Kix
10
-5(M
-1)
Binding costants of NAXs 1
1.770.48 0.51
7.07
10.048.90
7.48
0
2
4
6
8
10
12
Kix
10
-5(M
-1)
Binding costants of NAXs2
1D. Bhowmik, M. Hossain, F. Buzzetti, R. D’Auria, P. Lombardi, G.S.Kumar, J. Phys. Chem. B, 2012, 116, 2314−24.2D. Bhowmik, F. Buzzetti, G. Fiorillo, F. Orzi, T. Syeda Monir, P. Lombardi, G.S. Kumar, Med. Chem. Comm., 2014, 5, 226-31.
n = 3
n = 4
Berberine
DerivativesBinding to DNA
0
2
4
6
8
10
12
Ki x
10
-5 (
M-1
)
Pyridylalkyl derivatives
S. Chatterjee, S. Mallick, F. Buzzetti, G. Fiorillo, T. M. Syeda, Paolo Lombardi, K. Das Saha, G. S. Kumar, RCS Adv., 2015, 5, 90632
n = 5
Berberine DerivativesAntiproliferative effects
STO, MESOII = peritoneal mesothelima cell linesMSTO = pleural mesothelioma cell line
0123456789
IC50 [m
M]
Mesothelioma cell lines
STO
MESOII
MSTO
0
1
2
3
4
5
6
7
8
9
IC5
0 [m
M]
Mesothelioma cell lines
STO
MESOII
MSTO
Berberine DerivativesAntiproliferative effects
Human breast adenocarcinomacell line
Human liver hepatocellularcarcinoma cell line
S. Chatterjee, S. Mallick, F. Buzzetti, G. Fiorillo, T. M. Syeda, Paolo Lombardi, K. Das Saha, G. S. Kumar, RCS Adv., 2015, 5, 90632
In the Chinese traditionalmedicine, Berberine has been used for the treatment of hepatocellular carcinoma;
Berberine derivatives have an in vitro better effect.
Conclusions
The promising data obtained on relevant cancer cell lines, shown here andin other scientific reports, support an active role of BBR in inhibiting cancer cell
proliferation.
To improve this relevant property, many derivatives (essentially with (hetero)aromatic groups in the position 13 of the alkaloid skeleton) have been designed and synthesized.
In general, derivatives proved to be more efficient than the lead compound, thus opening new perspectives for drug discovery
Work performed so far has led to the identification of some candidate compounds with a profile that would justify the progression to late preclinicaldevelopment studies.
Aknowledgements: Financial supports were provided by Ministero dello Sviluppo Economico (Grant. 01709 ) under the 6th call of the EuroTransBio initiative, transnational project BERTA (BERberine as antiTumour Agents)