Mitomycin C analogs with a substituted hydrazine at position 7. Synthesis, spectral properties, and biological activity

Sawhney, K. N.; Kohn, Harold

doi:10.1021/jm00121a044

Cited by 6 publications

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“…Mitomycins are multifunctional molecules (). Although strategies to modify the C(7) ( − ) and N (1a) ( − ) loci exist, we chose to attach the antisense oligodeoxynucleotide to the C(10) site in the mitomycin (). Preliminary molecular modeling experiments indicated that mitomycins tethered at this site would permit subsequent DNA bonding at C(1) with minimal distortion of the DNA duplex .…”

Section: Resultsmentioning

confidence: 99%

“…The values for purines, pyrimidines, and porfiromycin at 260 nm were considered to be 14 000, 7000, and 12 000, respectively; the values for porfiromycin and DNA at 360 nm were considered to be 23 000 and 0, respectively (41,42) (40). Although strategies to modify the C(7) (44)(45)(46)(47) and N(1a) (48)(49)(50) loci exist, we chose to attach the antisense oligodeoxynucleotide to the C(10) site in the mitomycin (51). Preliminary molecular modeling experiments indicated that mitomycins tethered at this site would permit subsequent DNA bonding at C(1) with minimal distortion of the DNA duplex.…”

Section: Conjugation Of the N-[10-decarbamoyl-10-o-thiocarbonyl-[n(1a...mentioning

confidence: 99%

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Design, Synthesis, and Evaluation of Mitomycin-Tethered Phosphorothioate Oligodeoxynucleotides

et al. 1996

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Mitomycin C (1) is the prototypical bioreductive alkylating agent. Studies have shown that mitomycin C and its derivatives selectively alkylate guanine residues within di- and trinucleotide DNA sequences. This investigation sought to improve the selective DNA bonding properties of the mitomycins by coupling them with antisense oligodeoxynucleotides. Two procedures were developed that allowed the attachment of a phosphorothioate oligodeoxynucleotide containing a hexylamino spacer at the 5' terminus with a C(10)-activated mitomycin. In the first procedure, decarbamoylation of 1 (NaOCH3/ benzene) afforded 10-decarbamoylmitomycin C (10), which was treated with either dimethyl sulfate or methylthiochloroformate and base to yield 10-decarbamoylporfiromycin (11) and N(1a)-[(methylthio)-carbonyl]-10-decarbamoylmitomycin C (12), respectively. Activation of the C(10) site in 11 and 12 with 1,1'-carbonyldiimidazole or with 1,1'-thiocarbonyldiimidazole provided the N(1a)-substituted mitomycin 10-decarbamoyl-10-O-carbonylimidazoles (5, 7) and 10-decarbamoyl-10-O-thiocarbonylimidazoles (6, 8), respectively. Compounds 5-8 were reacted with glycine methyl ester hydrochloride (17) and base in both methylene chloride and aqueous buffered solutions to determine the ease and efficiency in which these C(10)-activated mitomycin derivatives coupled to amines. It was found that 5-8 all reacted with 17 in methylene chloride to give the coupled products 18-21 but that improved amine coupling yields in water were observed for the 10-decarbamoyl-10-O-thiocarbonylimidazoles 6 and 8 as compared with the 10-decarbamoyl-10-O-carbonylimidazoles 5 and 7. This finding led to the coupling of the phosphorothioate oligodeoxynucleotide, H2N(CH2)6-P(S)(OH)-GGCCCCGTG-GTGGCTCCAT (22) to 8. Compound 22 complemented a 19-base sequence in the translation initiation region of the human A-raf-1 gene. Use of excess 8 (28 equiv) with 22 gave only a 36% yield of the coupled product 23, which proved difficult to separate from 22. In the second procedure, phosphorothioate oligodexynucleotides that contained a hexylamino spacer at the 5'termini were coupled to 10-des(carbamoyloxy)-10-isothiocyanatoporfiromycin (9). Compound 9 was prepared in four steps from 11. Mesylation (methanesulfonyl chloride/pyridine) of 11 gave the C(10) mesylate 13, which was then treated with NaN3 (dimethylformamide, 90 degrees C) to give 10-des(carbamoyloxy)-10-azidoporfiromycin (14). Catalytic reduction (PtO2, H2) of 14 in pyridine afforded C(10) amine 15. Treatment of 15 with di-2-pyridyl thionocarbonate provided the desired 10-des(carbamoyloxy)-10-isothiocyanatoporfiromycin (9). Compound 9 readily coupled with 17 and base in both methylene chloride and aqueous buffered solutions to give 25. Use of the 5'hexylaminophosphorothioate oligodeoxynucleotides 32-35 in place of 17 gave the conjugated adducts 28-31, respectively, in a 12% to near-quantitative yield. The products were purified by semipreparative HPLC. Antisense agents 28-31 were designed to target a 30-base-long region from the c...

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Section: Resultsmentioning

confidence: 99%

Section: Conjugation Of the N-[10-decarbamoyl-10-o-thiocarbonyl-[n(1a...mentioning

confidence: 99%

Design, Synthesis, and Evaluation of Mitomycin-Tethered Phosphorothioate Oligodeoxynucleotides

et al. 1996

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“…The organic layer was washed with brine, dried over Na2S04, and concentrated on a rotary evaporator. The residue obtained was purified by preparative TLC (silica gel, 9:1 CHCl3-MeOH as a developing solvent) followed by trituration with CHCl3-7i-hexane and drying under vacuum to afford 12a (10 mg, 31%) as a red powder: NMR (270 MHz, pyridinedb) 2.17 (dd, J = 2.2, 4.6 Hz, 1 , 2-H), 2.25 (s, 3 H, la-CH3), 2.55 (d, J = 4.6 Hz, 1 H, 1-H), 3.20 (s, 3 H, 9a-OCH3), 3.48 (dd, J = 2.2, 12.6 Hz, 1 , 3 -), 3.60 (s, 3 H, 7-OCH3), 3.99 (dd, J = 4. 4, 11.3 Hz, 1 , 9-H), 4.22 (d, J = 12.6 Hz, 1 H, 3/3-H), 4.80 (br t, J = 10.9 Hz, 1 H, 10-Ha), 5.35 6.6-Dibromo-7-demethoxy-6-demethyl-7,7-(ethylenedioxy)-6,7-dihydromitomycin B (21).…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Antitumor Activity of Various 6-Demethylmitomycins and 6-Demethyl-6-halomitomycins

Arai

Ashizawa²,

Gomi³

et al. 1995

J. Med. Chem.

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A series of 6-demethylmitomycins and 6-demethyl-6-halomitomycins having various mitomycin skeletons were synthesized, taking into account the electronic effect toward the quinone moiety and the partition coefficients. Treatment of enones 15 and 16 with selenenamide or N-halosuccinimide-Et2NH afforded the 6-demethyl intermediates 17, 18, and 21-24 via the tandem Michael addition/retro-Mannich reaction sequence. Subsequent conversions into the mitomycin skeletons resulted in the formation of the desired derivatives 7a-c, 8a-c, 11a-c, and 12a,b. These mitomycin derivatives including 3a-c and 4a-c were evaluated for their anticellular activity against HeLa S3 cells and antitumor activity against Sarcoma 180 in mice. The anticellular activity of 1 and 3a-c depends on the substituent at the C-6 position and the order of increasing activity is H < CH3 < Br < Cl. A similar tendency was observed in their antitumor potency (ED50). The activities of 9 and 11a-c also follow a pattern similar to that of 1 and 3a-c. Compounds 4b,c, 8b,c, and 12b having both a halogen at the C-6 position and a methoxy group at the C-7 position did not show the activities because of the instability of the compounds. Interestingly, a correlation between the anticellular activity (IC50) and the partition coefficients (log kappa') determined by HPLC was observed within the compounds studied except the unstable compounds, while their antitumor activity (ED50 or T/C) did not correlate with the quinone reduction potential (E1/2). These results would indicate the importance of the C-6 substituents and the mitomycin skeletons for exhibiting both anticellular and antitumor activities.

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Synthesis and biological activity of novel mitomycin C analogs derived from mitomycin A

Kuroda

Hisamura

Matsukuma

et al. 1994

Journal of Heterocyclic Chem

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A variety of mitomycin C analogs were synthesized from mitomycin A and their biological activities were studied. Mitomycin A (1) underwent nucleophilic displacement reactions involving intramolecular hydrogen migrations upon treatment with nitrogen nucleophiles bearing mobile hydrogens, but the mode of hydrogen migration depended on the nature of the nucleophiles. The reaction with alkoxyamines gave compounds 6 and 7 which have the 5H‐6‐alkoxyimino‐4,7‐dione structure in ring A of 1. However, the reaction with hydroxylamine and benzoylhydrazine afforded compounds 11 and 13 which have the 4‐hydroxy‐6‐hydroxyimino‐7‐one structure and the 4‐hydroxy‐6‐hydrazono‐7‐one structure, respectively, in ring A of 1. These products were converted into various types of mitomycin C derivatives by methylation with methyl iodide or dimethyl sulfate. The mechanistic features of these reactions are discussed. The in vitro and in vivo biological activities were tested by using P388 leukemia and Sarcoma 180 tumor cells. Several of the synthesized compounds exhibited better activity than that of mitomycin C.

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Mitomycin C analogs with a substituted hydrazine at position 7. Synthesis, spectral properties, and biological activity

Cited by 6 publications

References 0 publications

Design, Synthesis, and Evaluation of Mitomycin-Tethered Phosphorothioate Oligodeoxynucleotides

Design, Synthesis, and Evaluation of Mitomycin-Tethered Phosphorothioate Oligodeoxynucleotides

Synthesis and Antitumor Activity of Various 6-Demethylmitomycins and 6-Demethyl-6-halomitomycins

Synthesis and biological activity of novel mitomycin C analogs derived from mitomycin A

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