- C(10) halogen 10-des(carbamoyloxy)porfiromycins: Synthesis, chemistry, and biological activity
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An efficient four-step procedure for the preparation of C(10) halogen 10-des(carbamoyloxy)porfiromycins 3-5 beginning with mitomycin C(1) is described. Solvolytic removal (NaOMe, MeOH/benzene) of the C(10) carbamoyl group in 1 followed by N-methylation (dimethyl sulfate (15 equiv), 1,8-bis(dimethylamino)naphthalene (15 equiv) in THF) provided 10-decarbamoylporfiromycin (7) in 65% yield. Treatment of 7 with methanesulfonyl chloride in pyridine gave 10-decarbamoyl-10-methanesulfonylporfiromycin (8) in 83% yield, which upon heating with metal halides (i.e., LiCl, LiBr, NaI) in either DMF or ethylene glycol dimethyl ether furnished the C(10) halogen 10-des(carbamoyloxy)porfiromycins 3-5 in 68-81% yields. The C(10) halogen 10-des(carbamoyloxy)porfiromycins served as useful starting materials for C(10)-modified derivatives. Treatment of the C(10) bromo derivative 4 with 1,8-diazabicyclo[5.4.0]undec-7-ene provided the elimination product, 10-des(carbamoyloxy)-9-dehydroporfiromycin (12), while addition of AgSCN to the C(10) iodo porfiromycin 5 led to the substituted adducts 10-des(carbamoyloxy)-10-thiocyanatoporfiromycin (10) and 10-des(carbamoyloxy)-10-thiocyanato-9-epi-mitomycin D (11). The C(10) halogen 10-des(carbamoyloxy)porfiromycins also underwent novel radical and thermal skeletal rearrangements. Treatment of the C(10) iodo derivative 5 with tributyltin hydride and A1BN led to the production of the ring-expanded quinone 14. Thermolysis of the C(10) bromo (4) and the C(10) iodo (5) adducts gave the tetracycles 18 and 19, respectively, in which the C(2) nitrogen bond in the starting porfiromycin had been preferentially cleaved in favor of the C(1) bond. Potential pathways for these rearrangements are briefly outlined. The in vitro cytotoxicities of 3-5 in human colon carcinoma cell lines were evaluated. All three C(10) halogen 10-des(carbamoyloxy)porfiromycins were noticeably less potent than mitomycin C.
- Choi,Yoo,Colson,Martin,Kohn
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- Synthesis of N-substituted 10-des(carbamoyloxy)-10-azidomitomycins
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A general method for the synthesis of N-substituted 10-des(carbamoyloxy)-10-azidomitomycins 5 has been developed. These compounds are expected to be rapidly converted to the corresponding C-10 isothiocyanate derivatives allowing mitomycins to couple to biomolecules. The key synthetic intermediate was 10-des(carbamoyloxy)-10-azidomitomycin C (12). Compound 12 was prepared by decarbamoylation of mitomycin C (1) followed by aziridine protection with Fmoc-chloride and activation of the C-10 site with methanesulfonyl chloride. Deprotection of the Fmoc unit with morpholine and treatment with NaN3 gave 12.
- Huh, Nam,Kogan, Timothy P.,Kohn, Harold
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- Synthesis of an oligodeoxyribonucleotide adduct of mitomycin C by the postoligomerization method via a triamino mitosene
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The cancer chemotherapeutic agent mitomycin C (MC) alkylates and cross-links DNA monofunctionally and bifunctionally in vivo and in vitro, forming six major MC-deoxyguanosine adducts of known structures. The synthesis of one of the monoadducts (8) by the
- Champeil, Elise,Paz, Manuel M.,Ladwa, Sweta,Clement, Cristina C.,Zatorski, Andrzej,Tomasz, Maria
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scheme or table
p. 9556 - 9565
(2009/02/02)
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- Electrochemical Reductive Activation of Mitomycin C
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We have used the electrochemical techniques of cyclic voltammetry and preparative flow cell electrolysis to study the role of one-electron vs. two-electron transfer in the reductive activation of mitomycin C (MC) and a primary mitosene metabolite, 1,2-cis-2,7-diamino-1-hydroxymitosene (6), to reactive intermediates in polar aprotic solvents.Cyclic voltammetry of MC in DMF (0.1 M TEAP) showed that MC undergoes two quasi-reversible electron-transfer processes at -0.937 and -1.410 V vs.Ag/AgCl, saturated KCl.A following chemical reaction appeared to occur after transfer of a second electron at -1.410 V as indicated by an anodic wave at -0.710 V and a cathodic wave at -0.800 V that appeared upon multicycle scanning.Flow cell reduction at -0.950 V vs.Ag/AgCl, 3 M NaCl over graphite, formed the radical anion of MC in DMF or Me2SO as characterized by EPR (g=2.0045).When the radical anion of MC in DMF was mixed with water, parent MC and at least eight other products were generated as detected by HPLC.The one-electron-reduction product profiles showed a pH dependence.Flow cell reduction of MC at -1.450 V formed the dianion of MC in DMF or Me2SO, which generated only two products when mixed with water.These products have been identified by mass spectral and NMR analyses to be 10-decarbamoyl-2,7-diaminomitosene (14) and 2,7-diamino-2,3-dihydro-6-methyl-1H-pyrroloindole-5,8-dione (22).Generation of 22 was completely suppressed when the dianion was added to phosphate buffer.Flow cell reduction of 6 in DMF at -1.200 or -1.500 V generated the radical anion (g=2.0045) or dianion, respectively.These species both gave 1,2-cis-2,7-diamino-2,3-dihydro-6,9-dimethyl-1-hydroxy-1H-pyrroloindole-5,8-dione (27) as the sole product when mixed with water.These data provide evidence that one-electron reduction is sufficient to activate MC and its primary metabolites to reactive intermediates.Furthermore, the results suggest that one-electron transfer is the dominant mode of bioreductive activation since the HPLC profile of the radical-anion-generated products of MC closely resembled the profile of metabolites generated from reduction with purified flavoenzymes.
- Andrews, Paul A.,Pan, Su-Shu,Bachur, Nicholas R.
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p. 4158 - 4166
(2007/10/02)
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- Lack of Influence of the Carbamoyl Group on the Stereochemistry of the Acid-Catalyzed Opening of the Aziridine Ring of the Mitomycins and of Congeners
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The acid-catalyzed opening of the aziridine ring of mitomycins A and C is known to occur predominantly with cis stereochemistry.We have observed that the presence or absence of a carbamoyl group at C-10 of mitomycin C and in certain of its analogues does not have a significant influence on the stereochemistry of the opening of this ring.The trans product obtained from mitomycin C was shown to be stable when treated with acid under the conditions of its formation.Mitomycin B was also shown to yield predominantly the cis product when it was subjected to acid-catalyzedopening of its aziridine ring.The 1H NMR spectra of acetate derivatives prepared from mitomycin B show two sets of signals that are due to two populations of rotamers.The analysis of these spectra has substantiated several previous spectral assignments.This paper also presents some thoughts on acid-catalyzed bifunctional DNA alkylation by mitomycins and 10-decarbamoyloxy-9-dehydromitomycins.
- Hornemann, Ulfert,Keller, Paul J.,Takeda, Kazuyoshi
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