Nachiket S Dighe*1, Shashikant R Pattan1, Deepak S Musmade1, Abhijeet N Merekar2,
Manisha S Kedar1, Deepak K Thakur1 and Pratik V Patel1
Pharmaceutical Chemistry, Pravara Rural
Many natural products from marine sources are endowed with promising anti cancer activity, thus representing invaluable leads in the plans for drug discovery. In this context, organic synthesis plays a decisive role in confirming (or revising) the chemical structures of the natural compounds allowing also access to suitable amounts of the target (and its analogs) for structure activity relationship (SAR) investigations. In this overview, we focus on the total and partial synthesis of anti cancer marine metabolites and their related compounds discussing the retro synthetic analysis of the strategies adopted.
Keywords: Marine, Anti Cancer Activity, Synthesis of Dictyostatin.
Cancer is a group of
diseases characterized by the disregulate
proliferation of abnormal cells that invade and disrupt surrounding tissues.
Being the second leading cause of death in the
A close analog of Taxol, Taxotere (docetaxel), is used in the treatment of lung and metastatic breast cancer. Unfortunately, treatment with taxanes isineffective in colon and prostate cancer and is associated with severe side effects. Besides cancer cells, other rapidly dividing cells, such as white blood cells and hair cells, are attacked by the antimitotic action of paclitaxel, and chemotherapy with Taxol is therefore accompanied by suppression of the immune system (neutropenia), deadening of sensory nerves (peripheral neuropathy), hair loss (alopecia), haematological toxicities, and adverse cardiac effects. The most severe limitation to the clinical application of Taxol is the emergence of tumor phenotypes resistant to taxanes as well as to other chemotherapeutic agents.
This phenomenon, known as multiple drug resistance (MDR), results from two mechanisms: (a) over-expression of the P-glycoprotein (PgP), an ATP-dependent efflux pump that lowers the intracellular concentration of cytotoxic products, on the surface of neoplastic cells; (b) Overexpression of tubulin isotypes that are less susceptible to induced polymerization and stabilization.3
Marine organisms, particularly sponge invertebrates and associated bacteria, are a prolific source of novel biologically active compounds with unusual, and often complex, structures. The harsh environment that marine sponges inhabit, together with their lack of physical defenses, requires that these organisms develop chemical deterrents to aid their survival. As a result, many of their associated secondary metabolites exhibit exceptional levels of biological activity, often combined with unique modes of action. However, the potential therapeutic utility of marine-derived natural products is hampered not only by the limited supply, but often also by their incomplete stereo chemical assignment. In both these respects, total synthesis can provide a powerful solution.
1. SYNTHESIS OF ELEUTHEROBIN 4 (Fig-1)
Sarcodictyins and eleutherobin (the “eleutheside” family of microtubule-stabilizing drugs, ) are active against paclitaxel-resistant tumor cell lines and therefore hold potential as second-generation microtubule-stabilizing anticancer agents. Their scarce availability from natural sources makes their total synthesis vital for further biological investigations.
This result contrasts sharply with many other Z-selective RCM reactions of diene cyclization precursors less densely functionalized than diene, which possessed protected and/or free alcohol functionalities at both the homoallylic positions and at only one allylic position. In the presence of a second-generation Grubbs catalyst, these dienes lead to the more stable Z-cyclized products under thermodynamic control.
2. SYNTHESIS OF DICTYOSTATIN 4 (Scheme-1)
The sponge-derived macrolide Dictyostatin has been reported to exhibit paclitaxel-like effects on cellular microtubules and to inhibit human cancer cell proliferation at low nanomolar concentrations and with activity superior to discodermolide (ED50 0.38 nM, P338 leukemia cells) . The structure of Dictyostatin with full stereo chemical assignments was recently established, and two total syntheses were completed in 2004 by the Paterson and the Curran groups. More recently, in 2006, Phillips and O’Neil reported another total synthesis, Curran and coworkers published a fluorous mixture synthesis of (–)-dictyostatin and three of its diastereomers, while Maier and coworkers described an alternative approach to the C1–C9 and C10–C23 segments of this interesting natural product. The development of a practical and flexible synthesis of dictyostatin is still an important goal, particularly as the natural supply is extremely scarce. With the recent withdrawal of discodermolide from clinical development, the importance of dictyostatin increases further. Our synthetic efforts toward dictyostatin were initially focused on the preparation of the C15–C23 fragment of the macrolide, containing 5 of its 11 stereocenters
3. SYNTHESIS OF SPIRASTRELLOLIDE A 5 (Fig-2) (Scheme-2)
2003, Andersen and coworkers reported the isolation of spirastrellolide
A from the
4. SYNTHESIS OF SARCODICTYIN 6 (Fig-3) (Scheme-3)
5. SYNTHESIS OF PACHASTRISSAMINE 7(Scheme-4)
(+)-Pachastrissamine a naturally occurring novel anhydrosphingosine derivative, has been isolated recently from the Okanawa marine sponge Pachastrissa sp (family calthropellidae) by Higa and co-workers1 and found to posses cytotoxicity at a level of IC50 0.01 μg/mL against P388, A549, HT29 and Mell 28 cell lines.
6. SYNTHESIS OF EPOTHILONES 8 (Fig-4)
A number of anticancer drugs possessing diverse molecular structures exert their cytotoxicity by disrupting microtubule dynamics. Most of these compounds, including the well-established chemotherapeutic agents colchicine, colcemid, podophyllotoxin, vinblastine, and vincristine operate by interfering with the formation and
growth of microtubules and preventing polymerization of
microtubules by diversion of tubulin into other types of aggregates thereby promoting net depolymerization and inhibition of cell proliferation at mitosis.
R=H= Epothilones A
R=Me= Epothilones B
7. SYNTHESIS OF PERICOSINES 9(Scheme-6)
Pericosines are unique C7 cyclohexenoid metabolites of Periconia byssoides OUPS-N133 fungus that was originally isolated from the sea hare, Aplysia kurodai. Pericosines show significant in vitro cytotoxicity against P388 lymphocytic leukemia cells. Pericosine A, in particular, shows the most potent activity and significant in vivo antitumor activity against P388 cells.
8. SYNTHESIS OF LAMELLARIN D 10 (Fig-5) (Scheme-7)
In 1985, Faulkner reported the isolation of a new class of marine natural product, isolated from a Lamellaria sp. of marine prosobranch mollusk. These compounds were called lamellarins and displayed potent inhibition of various protein kinases. Since the discovery of these original molecules, a total of 38 lamellarins were isolated from different ascidians.
9. SYNTHESIS OF BISTRAMIDE A 11 (Scheme-8)
A highly stereoselective and convergent total synthesis of bistramide A is described. The salient feature of this synthesis is the construction of the spiroketal subunit by hydrolysis of dialkylated tosylmethyl isocyanide derivative derived via alkylation of TosMIC with suitably substituted halohydrin derivatives.
10. SYNTHESIS OF EPOTHILONES B AND D12 (Scheme-9)
A highly convergent total synthesis of the natural products epothilone B and D is described. The route is highlighted by efficient generation of a C12−C13 trisubstituted olefin which exploits a sequential Nozaki−Hiyama−Kishi coupling and a stereoselective thionyl chloride rearrangement.
11. SYNTHESIS OF THE BCDE-TETRACYCLIC CORE OF (-)- CEPHALOTAXINE 13 (Scheme-10)
(-)-Cephalotaxine was isolated from the evergreen plum-yews of the genus Cephalotazus.1 This family exhibit antileukaemic activity. The BCDE tetracyclis core of (-)-cephalotaxine has been starting from N-Boc-Lpropine methyl ester. An alkylidene carbene 1,5-CH inserttion was used as a key step in the stereocontrolled synthesis of the spirocyclic fragment and an intramolecular Heck-type cyclisation was used to form the benzazepine ring.
12. SYNTHESIS OF PROPOSED AND REVISED AMPHIDINOLIDE W.14 (Scheme-11)
The isolation of amphidinolide W, a new cytotoxic 12-membered macrolide from the dinoflagellate Amphidinium sp., was reported in 2002. The absolute configuration at C-6 was determined by the advanced Mosher’s method, utilizing the secondary alcohol that was obtained by degradation of the Baeyer-Villiger oxidation product of amphidinolide W. Ghosh and co-workers synthesized proposed structure via a Yamaguchi macrolactonization, as illustrated in scheme. Chiral oxazolidone was alkylated to stereoselectively. Compound was transformed into amphidinolide w.
13. SYNTHESIS OF PROPOSED AND REVISED STRUCTURES OF OBYANAMIDE.15 (Scheme-12)
A cytotoxic depsipeptide designated as obyanamide was isolated from the marine cyanobacterium Lyngbya confervoides, as shown in Scheme . Compared to related natural products, in the originally proposed structure it had an unexpected (S)-configuration at C-3. The stereochemistry at C-3 in the Apa (aminopentanoic acid) part was deduced by chemical degradation and comparison of the hydrolyzated mixture with synthetic standards due to the limited amount of available material. Methyl (S)-N-Boc-3-aminopenatanoate, derived from (S)-2-aminobutyric acid via a Wolff rearrangement, was combined with ester to afford amide. A Yamaguchi esterification afforded ester, which was cyclized to give the desired. But this total synthesis suggested the need for structural revision. Since all other related compounds isolated from the Lyngbya species had R-configuration in the β-amino acid residues, the same research group thought the revised structure should be obyanamide. Thus they carried out the total synthesis of this using the same strategy.
15. SYNTHESIS OF REVISED DOLASTATIN. 17 (Scheme-14)
Dolastatin is a cancer cell
growth inhibitor isolated from the sea hare Dolabella
auricularia collected in the
Natural products traditionally have played a pivotal role in drug discovery and in particular the uniqueness of marine metabolite core structures makes these compounds of interest in the development of pharmaceutical agents, in particular the anticancer here discussed. In these studies, chemical synthesis still represents a route of choice showing its potential to confirm or revise the chemical structures of the natural products and to allow the access to related compounds for structure activity relationship investigations. The actual interest in this field is confirmed by several reports on the synthesis of marine natural products with anti cancer activity. This overview focuses on the main aspects of such reports strongly relying on the corresponding retro synthetic sequences.
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