Cytotoxic polyketides

In 1997 (-)-callystatin A (Fig. 1.2.2), a potent cytotoxic polyketide, was isolated from the marine sponge Callyspongia truncata and structurally elucidated by Ko-bayashi et al. [20] shortly afterward its absolute configuration was confirmed by the same authors by total synthesis [21]. The structure of (-)-callystatin A shows a polypropionate chain and a lactone ring connected to each other by two diene systems separated by two sp carbon atoms (Fig. 1.2.2). Since this arrangement is structurally related to several antitumor antibiotics and due to the fact that only very small amounts can be isolated from natural sources, callistatin A has been... 

In the marine environment, several polyketides with important medicinal value have been reported in recent years. They have been isolated mainly from marine sponges of the genus Caltyspongia and Plakortis, which yielded potent cytotoxic polyketides, e g., callystatin A, Fig. (52) isolated from Callyspongia trunccitci [285,431], and several cyclic polyketides named plakortides, Fig. (53), isolated from Plakortis lita [432] and Plakortis simplex [433],... 

These polyketides, plakortides, have also been shown as potent activators of cardiac calcium-pumping ATPase [434], New cyclic polyketides were recently isolated from the Red Sea marine sponge Acarnus bergquistae [435], while cytotoxic polyketides have also been reported from sea hares of the genus Aplysia and Dolabella [436], and the marine sponge The one Ha swinhei [437],... 

Chemical study of a marine-derived Penicillium brocae, obtained from a tissue sample of a Fijian Zyzzya sp. sponge, resulted in the isolation and characterization of three novel cytotoxic polyketides, brocaenols A-C 136, 137a, and 137b, possessing an unusual enolized oxepine lactone ring system <2003JOC2014>. 

Callystatin A (4) is a higly potent cytotoxic polyketide isolated from Callyspongia truncata Its absolute structure was determined by chemical method and confirmed by total synthesis. Its potent cytotoxicity (IC50 = 0.022 nmol against human pharyngeal carcinoma KB cells) was presumed to be due to the inhibition of nuclear export signal (NES)-dependent export of nuclear proteins. ... 

Lasonolide A was reported in 1994 as a cytotoxic polyketide macrolide isolated from the sponge Forcepia sp. collected in the British Virgin Islands. " The structure of lasonolide A containing seven double bonds was proposed from the NMR data. Although all the double bonds were disubstituted olefins, one of those was... 

Clinical development is hampered due to the extremely scarce supply of discodermolide from the natural source. Thus, total synthesis provides the only viable route to useful quantities of this novel cytotoxic polyketide. Consequently, there have been considerable synthetic efforts toward the total synthesis of discodermolide [16], Up to date, five total synthesis of (+)- and/or (-)-discodermolide have been reported, one by Schreiber [3], one by Smith [17], one by Myles [18], one by Marshall [19] and one by Paterson [20]. All the syntheses are convergent. Schreiber and Myles employed an analogous connection by using a Nozaki-Kishi addition of a C8 acetylenic or (Z)-vinylic chromium to a C7 aldehyde for the major... 

Members of the family Annonaceae, the custard apple family, are widely distributed and the subject of numerous phytochemical investigations. Earlier studies of various Annonaceae have resulted in the isolation and identification of a number of aporphine alkaloids. Recently a series of novel, cytotoxic polyketides containing tetrahydrofuran and y-lactone groups have been discovered (ref. 46-49). 

Figure 4. Cytotoxic Polyketides from Annona NaBH4...

Hong H, Demangel C, Pidot SJ, Leadlay PF, Stinear T (2008) Mycolactones immunosuppressive and cytotoxic polyketides produced by aquatic mycobacteria. Nat Prod Rep 25 447 54... 

Discodermolide (36) is a cytotoxic polyketide isolated in low yield from the Caribbean sponge Discodermia dissoluta 44), The recent discovery that discodermolide shares the same microtubule-stabilising mechanism of antimitotic action as the clinically important anticancer drug, Taxol (paclitaxel), and retains activity against Taxol -resistant cancer cells has stimulated considerable interest (45,46). Due to the scarce supply of the natural material, the development of an efficient total synthesis (47-52) of (+)-discodermolide is needed to provide useful quantities for further testing, as well as enabling access to structurally simplified analogues. 

Asolkar, R.N., Jensen, P.R., Kauffman, C.A., and Fenical, W. (2006) Daryamides A-C, weakly cytotoxic polyketides from a marine-derived actinomycete of the genus Streptomyces strain CNQ-085./. Nat. Prod., 69, 1756-1759. 

Schneemann, I., Kajahn, I., Ohlendorf, B., Zinecker, H., Erhard, A., Nagel, K., Wiese, J., and Imhoff J.F. (2010b) Mayamydn, a cytotoxic polyketide from a Streptomyces strain isolated from the marine sponge Halichondria panicea. J. Nat. Prod., 73, 1309-1312. 

Murakami, N., Wang, W.Q., Aoki, M., Tsutsui, Y, Sugimoto, M., and Kobayashi, M. (1998) Total synthesis of callystatin A, a potent cytotoxic polyketide from the marine sponge, CaUfspongia tmneata. Tetrahedron Lett., 39, 2349—2352. 

Use of these chiral allenyl metal reagents for the introduction of a propar-gyl group allows the synthesis of all four diastereomeric permutations of dipropionate subunits. The propargyl unit also provides a convenient handle for further elaboration, as demonstrated in Marshall s synthesis of the cytotoxic polyketide discodermolide (182, Scheme 5.30) [115]. Propargylation of aldehyde 177 with an allenylzinc species derived from mesylate 172 furnishes anti product 178 in 90 10 dr. The addition of allenylstannane 180 to aldehyde 179 affords the syn product 181 in an impressive 97% yield and >95 5 dr. 

The isopropoxide-derived catalyst developed by Keck generally displays broader substrate scope, and has consequently found greater use in synthesis [30, 32]. Keck has documented an application involving the coupling of stannane 199 with aldehyde 198 to give adduct 200 in 78% yield and 99% ee (Scheme 5.32) [124]. This transformation was a key strategic step in the total synthesis of the potent cytotoxic polyketide rhisoxazin D (201). 

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