Manumycins

THREE-MEMBERED HETEROCYCLIC RINGS AND THEIR FUSED DERIVATIVES 

Biosynthetic studies on this family of antibiotics were conducted in parallel on the major components of the group, namely manumycin 220 and asukamycin 221, because of their remarkable similarities, although they differ from each other in the nature of their side chains. 

The upper side chain of 220 was labeled by incorporation of [l- C]acetate at positions C-F, C-3, C-5, C-7 and C-9. Feeding with [2- C]acetate showed significant labeling of C-1F, C-12, and C-13, as well as the noticeable distribution of the label over the whole chain with the exception of C-1 and C-9. A feeding 

Evaluation of the above-described experiments led to polyketide-type pathways for the biosynthesis of the side chain units of 220 and 221, differing in the nature of the chain starter and extension units. In the case of 220, the upper side chain (C-1-C-13 ) was predicted to arise from an acetate starter unit that is elongated by condensation with one malonyl-CoA and three methylmalonyl-CoA ( propionate ) units. For 221, in the upper chain (Cl -C13 ), the starter unit was presumed to be 

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The formation of the epoxide moiety found in a number of compounds from the manumycin group of antibiotics (Scheme 10.22) might proceed through a similar... 

Scheme 4.51. Synthesis of trienes related to asukamycin and manumycin A side chains.

Chatterjee and coworkers45 recently reported the taxonomy, production, isolation, structure elucidation and biological properties of a new antibacterial antibiotic alisamycin (75), a new member of the manumycin group of antibiotics obtained by the fermentation of Streptomyces actuosus. 

The myxobacterium Chondromyces crocatus contains the novel chondrochlo-rens A (831) and B (832) (879). A marine Streptomyces species has afforded the manumycin antibiotics chinikomycins A (833) and B (834) (880). While inactive in antiviral, antimicrobial, and phytotoxicity screens, these chinikomycins display some cytotoxic activity. 

Block O, Klein G, Altenbach H-J, Brauer DJ (2000) New Stereoselective Route to the Epoxyquinol Core of Manumycin-Type Natural Products. Synthesis of Enantiopure (+)-Bromoxone, (-)-LL-C10037a, and (+)-KT 8110. J Org Chem 65 716... 

Thereafter, these methodologies were extended to the preparation of o-quinone monoacatals (2b) [32-34] [Eq. (2)], and have been utilized widely for total syntheses of natural products such as miroestrol (4),thielocin Al (5),dyne-micin A (6), manumycin (7), nisamycin (8), xestoquinone (9), calicheamicinone (10), and asatone (11). 

The manumycin family were isolated from Streptomyces parvulus (Tii 64) and possess a wide range of biological properties. Taylor and co-workers synthesized manumycin A (7) via the quinone monoacetal (131), which was prepared by PIDA oxidation, followed by epoxidation and alkylation on the cyclohexa-dienone (130) [90] (Scheme 8). Other members of the mamumycin family of antibiotics such as alisamycin, asukamycin, and ( )-nisamycin (8) have been synthesized by similar strategies [91]. 

Hu W, Wu W, Yeung SC, Freedman RS, Kavanagh JJ, Verschraegen CF. Increased expression of heat shock protein 70 in adherent ovarian cancer and mesothelioma following treatment with manumycin, a farnesyl transferase inhibitor. Anticancer Res 2002 22 665-672. 

Two different epoxidation reactions have been studied using chiral phase transfer catalysts. The salts 22 and 23 have been used to catalyse the nucleophilic epoxidation of enones (e.g. 24) to give either enantiomer of epoxides such as 25 (Scheme 9) [17]. Once again, the large 9-anthracenylmethyl substituent is thought to have a profound effect on the enantio selectivity of the process. A similar process has been exploited by Taylor in his approach to the Manumycin antibiotics (e.g. Manumycin C, 26) [18]. Nucleophilic epoxidation of the quinone derivative 27 with tert-butyl hydroperoxide anion, mediated by the cinchonidinium salt la, gave the tx,/ -epoxy ketone 28 in >99.5% ee (Scheme 10). 

The extremely broad functional group tolerance of the Pd-catalysed N-de protection of Aloe groups was a crucial design feature in a synthesis of the epoxy-quinol core of the Manumycin family of antitumour antibiotics [Scheme 8,80].195 Note the convenient generation of the Pd(0) catalyst in situ from reaction of dichlorobis(triphenylphosphine)palladium(II) with tributylstannane. The use of sodium borohydride and borane dime thy lamine complex is illustrated in Schemes 8.81193 and 8.82194 respectively. 

The fungal metabolite scyphostatin (Fig. 7) is a potent, reversible inhibitor of membrane-bound Mg +-dependent neutral sphingomyelinase (nSMase), thereby interfering with the generation of ceramide (102, 103). The activity of nSMases is sensitive to the cellular redox state, for example, the ratio of glutathione in the reduced versus the oxidized form (104, 105). The famesyltransferase inhibitor manumycin A, a polyenamide produced by the Streptomyces species, also inhibits nSMase irreversibly (106). 

HJ, Giannis, A. Manumycin A and its analogues are irreversible inhibitors of neutral sphingomyelinase. ChemBioChem. 2001 2 141-143. 123. 

In 1998, Wynberg s epoxidation procedure using chiral phase-transfer catalysts was applied by Taylor and coworkers to the total synthesis of (+ )-manumycin A [19], (—J-alisamycin [20], and (+ )-MT 35214 [20] (Scheme 5.14). The epoxidation... 

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