The syntheses and reactivity of N-TBDPS and N-trityl protected derivatives of an aziridinomitosene corresponding to FK317 are described. New reactivity patterns were observed for these highly sensitive and functionally dense heterocycles under mild nucleophilic conditions approaching the threshold for degradation. Thus, the silyl or trityl protected aziridinomitosene reacted with Cs(2)CO(3)/CD(3)OD to give isomeric products where substitution occurred at C(10) and C(9a) (mitomycin numbering) providing a CD(3) ether and a CD(3) hemiaminal, respectively. These findings show that heterolysis at C(10) is faster than at aziridine C(1), in contrast to the behavior of typical aziridinomitosenes in the mitomycin series. The labile N-TBDPS hemiaminal and the more stable N-trityl hemiaminal resemble the mitomycin K substitution pattern. A reagent consisting of CsF in CF(3)CH(2)OH/CH(3)CN desilylated a simple N-TBDPS aziridine but caused nucleophilic cleavage at C(1) as well as C(10) without cleavage of the N-TBPDS group in the fully functionalized penultimate aziridinomitosene. The high reactivity of the C(10) carbamate with nucleophiles precludes the use of deprotection methodology that requires N-protonation for fully functionalized aziridinomitosenes in the FK317 series.

01 Oct 2004·The Journal of Organic ChemistryQ2 · CHEMISTRY

A Synthetic Approach toward the Proposed Tetracyclic Aziridinomitosene Derived from FK317

Q2 · CHEMISTRY

Article

Author: Kim, Musong ; Vedejs, Edwin

A synthesis of the FK317 derivative 25 is described using internal Michael addition. Tin-lithium exchange of the deuterated stannylaziridine 18 generated the key lithioaziridine intermediate, followed by cyclization and aromatization of the pyrrole ring to give 7. Ester reduction from 7 to 23 was effected via temporary aldehyde protection as the silylimidazole adduct 22, and conversion to the carbamate 25 was carried out using FmocNCO and FMOC cleavage. Structure 25 is the N-trityl-protected derivative of the proposed intermediate from bioactivation of FK317 that is responsible for DNA cross-linking. Attempted nitrogen deprotection of 25 using MsOH/i-Pr(3)SiH resulted in replacement of the C(10) carbamate by hydride. Deprotection of the more stable 21 gave the desired aziridine 26.

01 Dec 2003·BiochemistryQ3 · BIOLOGY

Interstrand Cross-Linking of DNA by FK317 and Its Deacetylated Metabolites FR70496 and FR157471

Q3 · BIOLOGY

Article

Author: Ducept, Pascal ; Williams, Robert M.

FR900482 (1) and FR66979 (2) are structurally novel natural products isolated by Fujisawa in 1987 and have been shown to be highly potent antitumor antibiotics structurally related to the mitomycins. Studies on the mode of action have established that these new agents form covalent DNA interstrand cross-links both in vitro and in vivo as a result of the reactive mitosene intermediate generated upon bioreductive activation. Semisynthetic analogues such as FK973 (3) and FK317 (4) were developed in the search for potentially superior clinical candidates. Although FK317 has been shown to be a potent compound, to date no direct evidence of DNA interstrand cross-link sequence specificity has been reported. In this study, DNA interstrand cross-links were generated by treatment of a synthetic duplex DNA substrate with FK317 (4) and its deacetylated metabolites FR70496 (5) and FR157471 (6). Analysis by gel electrophoresis revealed the formation of orientation isomers displaying electrophoretic mobility vastly greater than the mobilities of those generated from FR900482 (1). Despite these differences, it was established by Fe(II)-EDTA footprinting that FK317 (4) as well as 5 and 6 forms DNA interstrand cross-links within the expected 5'CpG3' step, clearly demonstrating that the phenolic hydrogen in 1 and 2 is not a prerequisite for efficient DNA interstrand cross-linking by the FR class of compounds.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 2	-	Astellas Pharma, Inc.	-
Solid tumor	Phase 2	JP	Fujisawa Pharmaceutical Co., Ltd.	-

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