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New Drug

Discovery

by

Md. Monirul Islam

Pharmacy Discipline

Khulna University

Bangladesh

1. Introduction

Humans have long sought medicines, antidotes, palliatives and other bioactive materials

that positively affect health from their environment. From early medicinal treatments such

as willow bark tea for pain to the far more efficacious current-day pharmaceuticals which

include cholesterol lowering statins, anti-cancer drugs, narcotic analgesics such as the

opioids and non-narcotic analgesics such as ziconitide, or antibiotics are directly derived

from natural product research. Research and successful development of pharmaceutical

agents continues to remind us that the natural world remains an incompletely mined source

of novel pharmaceutical agents. The marine environment has been less effectively mined to

date than terrestrial environments due to its inherent inaccessibility and the difficulty of

preserving and transporting samples from their origin to the laboratory. The marine

environment represents a unique evolutionary niche yielding unique bioactive molecules.

2. New drug discovery from marine sources

Discovery of novel natural products is an accepted method for the elucidation of

pharmacologically active molecules and drug leads. Natural products from filter feeding

marine invertebrates and in particular, sponges, have proven to be a rich source of

structurally unique pharmacologically active compounds, with over 16,000 molecules

isolated thus far and a continuing pace of discovery at hundreds of novel bioactive

molecules per year. All classes of pharmaceuticals have been represented in this discovery

process, including antiprotazoals, TGF-beta inhibitors, cationic channel blockers, anticancer,

cytotoxic, antiviral, anti-inflammatory and antibacterial compounds.

3. Sources of marine natural products

There have been reviews on aspects of the chemistry and bioactivity of compounds from

microbes, soft corals, cyanobacteria and microalgae, sponges, echinoderms, ascidians, fish,

the sponge genus Halichondria, terpenes from the soft coral genus Sinularia, coelenterates,

tunicates, opisthobranch mollusks, echinoderms.

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4. Marine natural products being the new source of lead compounds

Marine organisms have evolved to produce distinct and dynamic molecular responses due

to the stressors in their environment, such as nearly ubiquitous bacterial and viral

competition and attack, and continuously variable environmental parameters such as

salinity or pH. Additionally, marine organisms tend to share a higher degree of networked

interconnectedness than land organisms, and do not suffer from degenerative diseases

similar to mammalian life. As example, aging mechanisms differ or are absent (i.e., no

telomere shortening is observed), and cancer and cardiovascular disease (or more

accurately, its equivalent) are unobserved. Thus, the marine ecosphere may be considered a

unique evolutionary niche which has given rise to a dynamic, diverse type of novel

molecular structures.

5. Marine natural products as drugs

5.1. Eribulin mesylate

Eribulin isolated from Halichondria okadai was

approved by FDA in 2010 to treat patients with

metastatic breast cancer who have received at

least two prior chemotherapy regimens for late-

stage disease.

Fig: Structure of eribulin.

5.2. Discodermolide

Discodermolide, a polyhydroxylated lactone

structure, was isolated from the marine sponge

Discodermia dissoluta and originally found to have

immunosuppressive activity. (+)-Discodermolide is

now in Phase I clinical trials as a potential drug for

solid tumors. Fig: Structure of discodermolide.

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5.3. Dolastatin-10

Dolastatin-10 and its related congener

Dolastatin-15 are polypeptide natural

products which were isolated from

marine sea hare Dolabella auricularia.

Both of these compounds are more

potent than vinblastine in tubulin

polymerization assays. Fig: Structure of dolastatin-15.

5.4. Didemnin B

Didemnins are cyclic depsipeptide compounds

isolated from a tunicate of the genus Trididemnum

that were collected in the Caribbean Sea. Didemnin B

is the one that possesses the most potent biological

activities. This compound, though, is too toxic to be

useful as antiviral or immunosuppressive agent; it has

been in Phase I clinical trials as an anticancer agent.

Phase II clinical trials are underway.

Fig: Structure of didemnins.

5.5. Bryostatin 1

The Bryostatins are macrocyclic lactones isolated from

the marine bryozoan Bugula neritina and found to

possess both antineoplastic and immunopotentiating

properties. Bryostatin 1 was originally described on

the basis of inhibiting growth in murine P388

lymphocytic leukemia cells at subnanomolar

concentrations. A range of properties have

subsequently been described including activation of T-

cells, immunomodulation and stimulation of

haematopoietic progenitor cells. Fig: Structure of bryostatin.

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5.6. Manzamine A

Manzamine A, a beta-carboline alkaloid present in

several marine sponge species, has potent

inflammatory activity, antifungal, anti-HIV-I

activities with moderate antitumor activity. These

compounds were isolated from E. rufescens. The

anti-malarial effect of manzamine A was due to

inhibition of the growth of the rodent malaria

parasite Plasmodium berghei in vivo.

Fig: Structure of manzamine.

6. Future aspects of marine natural products

The marine environment, a virtually untapped resource to date, holds great promise as a

rich source of novel bioactive molecules, for discovery of both novel pharmaceutical agents

and nutraceuticals, which have significant overlap with pharmaceuticals (as example,

carotenoids can function as antioxidants, or as various potent cytotoxic agents). Mining

genomes to discover such novel, bioactive natural products is a powerful and effective

discovery modality that is actively being developed by laboratories around the world. The

goal is to conduct, as available, whole genome, proteome, transcriptome, lipidome or

metabolome analyses to discover novel marine bioactive, pharmaceutical, and nutraceutical

agents, with the overall vision and goal of improving human health.

7. Conclusion

Natural products have played a significant role in drug discovery. Over the past 75 years,

natural product derived compounds have led to the discovery of many drugs to treat human

disease. Drugs developed from marine sources give us this hope and also give us novel

mechanisms to fight some of the most debilitating diseases encountered today, including:

HIV, osteoporosis, Alzheimer’s disease and cancer.

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8. References

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Publishers. ISBN 1-4020-3472-5 and ISBN 1-4020-3484-9 (e-book). 2005.

2. Joseph, B.; Sujatha, S. Pharmacologically Important Natural Products from Marine

Sponges. J. Nat. Prod. 2011, 4, 05-12.

3. Orhan, I.; Şener, B.; Kaiser, M.; Brun, R.; Tasdemir, D. Inhibitory Activity of Marine

Sponge-Derived Natural Products against Parasitic Protozoa. Marine Drugs 2010, 8, 47-58.

4. Fenical, W. Natural Products in the Marine Environment. Science 1982, 215, 4535, 923-

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5. Cragg, G.; Newman, D.; Snader K. Natural Products in Drug Discovery and Development. J.

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7. NP.Searcher http://dna.sherman.lsi.umich.edu.

8. Wikipedia free encyclopedia website: http://en.wikipedia.org

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