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.

01 Jan 2003·The Journal of Organic ChemistryQ2 · CHEMISTRY

Formal Enantiospecific Synthesis of (+)-FR900482

Q2 · CHEMISTRY

Article

Author: Rapoport, Henry ; Paleo, M. Rita ; Aurrecoechea, Natalia ; Jung, Kang-Yeoun

The enantiospecific synthesis of FK973, and thus a formal enantiospecific synthesis of the antitumor antibiotic (+)-FR900482, is reported. Addition of aniline 8 to chiral epoxide 9, prepared from l-vinylglycine, afforded amino alcohol 12. After protection of the aliphatic nitrogen with the 9-phenylfluoren-9-yl group, to preserve the acidic stereocenter from racemization, formation of the aziridine 14 and intramolecular condensation under basic conditions gave azocinone 15. Hydroxymethylation at the benzylic position was achieved by a process involving methylenation, epoxidation, and hydrogenolysis; the absolute stereochemistry of the resulting alcohol 23 was determined by X-ray crystallographic analysis. The hydroxyl group of 23 was carbamoylated, and the aromatic amine was deprotected electrochemically and then oxidized to give an unstable hydroxylamine that was immediately protected as acetate 26. Oxidation of 26 with DMP, followed by hydrazinolysis of the acetyl group led to spontaneous closure of the resulting N-hydroxyamino ketone to hemiketal 28, which can be considered as a fully protected precursor of FR900482 and derivatives. Acid treatment to remove the protecting groups and acetylation afforded the triacetate FK973.

06 May 1998·Cancer Chemotherapy and PharmacologyQ4 · MEDICINE

FK317: a novel substituted dihydrobenzoxazine with potent antitumor activity which does not induce vascular leak syndrome

Q4 · MEDICINE

Article

Author: Inami, Masamichi ; Nishigaki, Fusako ; Tsujimoto, Susumu ; Miyayasu, Kikuo ; Naoe, Yoshinori ; Manda, Toshitaka ; Shimomura, Kyoichi ; Kawamura, Ikuo ; Matsumoto, Sanae

PURPOSEFK973, a substituted dihydrobenzoxazine, is an antitumor antibiotic which has shown high therapeutic efficacy in a phase I study, but its development has been abandoned because of the side effect of vascular leak syndrome (VLS) in the clinical study. This study was performed to investigate whether or not FK317, a new benzmethoxy derivative of FK973, retains the antitumor activity of FK973 without the side effect of VLS.METHODSVLS was evaluated by the volume of pleural effusion in rats. Cytotoxic activities were determined by a tetrazolium-based colorimetric assay (MTT assay) against murine (B16, P388) and human (HeLa S3, KB) tumor cell lines. Antitumor activities against murine ascitic leukemia (P388, L1210), murine solid tumors (reticulum cell sarcoma M5076, Colon 38 carcinoma) and human xenografts (mammary carcinoma MX-1, lung carcinoma LX-1) were examined.RESULTSFK973 (1.8 mg/kg) given i.v. to rats induced pleural effusion, one of the elements of VLS, 36 days after the first dosing, but did not 28 days after dosing. This model reflects clinical VLS delayed-type effusion with high protein concentrations. In contrast, FK317 (1.0-3.2 mg/kg) did not induce pleural effusion at all. FK317 had stronger cytotoxic effects against in vitro cultured B16, P388, HeLa S3 and KB tumor cell lines, and in in vivo experiments, FK317 showed equivalent antitumor activity against P388, M5076 and MX-1, and more potent antitumor activity against L1210, Colon 38 and LX-1 compared with FK973.CONCLUSIONThese results suggest that FK317 retains the antitumor activity of FK973 and does not induce VLS, and FK317 is a drug with high clinical potential for treating tumors in humans.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 1	JP	Fujisawa Pharmaceutical Co., Ltd.	-
Neoplasms	Phase 1	-	Astellas Pharma, Inc.	-

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