Antitumor agents mitomycin

The rationale for the cyclopent[Z>]indole design discussed above was that the quinone methide would build up in solution and intercalate/alkylate DNA. Enriched 13C-NMR studies indicate that the quinone methide builds up in solution and persists for hours, even under aerobic conditions (Fig. 7.21). In contrast, the quinone methide species formed by known antitumor agents (mitomycin C) are short lived and highly reactive. The spectrum shown in Fig. 7.21 also shows the N to O acyl transfer product that we isolated and identified. However, we could not determine if the quinone methide structure actually has the acetyl group on the N or O centers. 

Schacht and coworkers in Belgium201-212 used pellets of a polyphosphazene with both ethyl glycinate and ethyl phenylalanate side groups for the controlled release of the antitumor agent, mitomycin-C. A 100% ethyl glycinato polymer released the drug too rapidly, but mixed-substituent polymers with 50-65% phenylalanine ester released the drug at an optimum rate. 

Antitumor agents mitomycin A (61 A) and mitomycin C (61C) contain a latent quinone functionality, which is exposed by reductive activation and elimination of a glycoside or an alcohol followed by opening of the aziridine ring. These quinone methides then react with nucleic acids to form bis-adducts.103 The reductive activation of mitomycins provides selectivity in targeting solid tumors, because this is favored in the oxygen-deprived environment of tumor cells, and inhibited by the oxygen-rich environment of healthy tissues.107... 

Tomasz, M. Palom, Y. The mitomycin bioreductive antitumor agents cross-linking and alkylation of DNA as the molecular basis of their activity. Pharmacol. Ther. 1997, 76, 73-87. 

Lim and Sulikowski (84) explored the intramolecular C-H insertion in 119 alpha to the nitrogen atom as a rapid entry to the mitomycin skeleton and the antitumor agent FR-900482. Rhodium(II) based catalysts provide nearly racemic products. Bis(oxazoline) (55b) affords highest selectivities in this system and chloroform was found to be the optimal solvent, Eq. 71. The authors note that the reaction is somewhat capricious. 

Compounds whose structures include a quinone moiety have been intensively investigated as potential antitumor agents. At least two quinones, mitomycin C and diaziquone, that have found their way to the clinic. These compounds in addition include a reactive aziridine ring. A recent entry that incorporates both those features, apaziquone (135), also known as E09, may be viewed as an oxidized indole. In the key reaction of a succinct synthesis to this agent, quinone 129 is allowed to react with... 

The new examples reported include the preparation of antiviral, antibacterial, and antitumor agents by coupling sugar isothiocyanates and such biologically active amines as triazole derivatives,195 mitomycin,196 isothia-zolopyrimidines,40 and also platinum compounds.197 Other A -nuclcophiles such as hydrazine,37 isothiourea,198 and guanidine derivatives199 have been similarly coupled to sugar isothiocyanates. 

Antitumor antibiotics bleomycin, enediynes, and mitomycin 05CRV739. Hybrid molecules based on distamycin A as potential antitumor agents 06ARK(7)20. 

FR-900482 918, a mitomycin-like antitumor agent, isolated from Streptomyces sandaensis, exists as a 2 1 mixture f> a ether bridge) of stereoisomers at neutral pH, but almost exclusively as the j8-isomer in acidic media. An asymmetric route to its core nucleus involves the cyclization of an aziridinyl radical derived from 914 to give a functionalized indole nucleus 915 —> 916. In a further step, a bmzyloxy-carbonyl group is introduced on the primary alcohol function using CDI and benzyl alcohol, affording 917 in 71% yield [659]. 

Streptomyces caespitosus produces several mitomycins, antibiotics that show an excellent antitumor activity but of limited utility because of their toxicity. The only substance acceptable for human use is mitomycin C, approved by FDA in 1974. Mitomycin C acts by forming covalent bridges across two opposite DNA strands, causing a rapid cell death (Tomasz 1995). In contrast to most antitumor agents, it is also active against the hypoxic cells in the core of solid tumors and therefore is indicated for the treatment of specific type of neoplasms such as gastric, colorectal, and lung cancer. 

Antitumor antibiotics are amongst the most important of the cancer chemodierapeutic agents, which include members of the anthracycline, bleomycin, actinomycin, mitomycin and aureolic acid families. Clinically useful agents from these families are the daunomycin-... 

Camptothecin analogs Irinotecan Topotecan Epipodophyllotoxins Etoposide Teniposide Antitumor antibiotics Bleomycin Dactinomycin Daunorubicin Doxorubicin Epirubicin Idarubicin Mitomycin Mitoxantrone Valrubicin Microtubule agents Docetaxel Paclitaxel Vinblastine Vincristine Vinorelbine Enzymes Asparaginase Pegasparaginase Metals... 

Mitomycin C is a natural product sometimes classified as an antitumor antibiotic (see Table 124—15). It has functional similarities to nitrogen mustard compounds and may function as an alkylating agent, although its toxicity pattern differs from conventional alkylators. 

Paz, M.M., Das, A., and Tomasz, M., Mitomycin C hnked to DNA minor groove binding agents synthesis, reductive activation, DNA binding and cross-hnking properties and in vitro antitumor activity, Bioorg. Med. Chem., 7,2713,1999. 

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