Introduction of Z-GP scaffold into procarbazine reduces spermatoxicity and myelosuppression.

Incorporation of carbobenzoxy-glycylprolyl (Z-GP) to either α or ß position of the hydrazine moiety in procarbazine (Pcb) has been carried on in 5-steps process. The overall yield was 32.7%. The new entity Z-GP-Pcb was confirmed targeting to fibroblast activation protein-α (FAPα). Z-GP-Pcb may be hydrolyzed by either isolated rhFAPα or tumor homogenate. It was shown far less cytotoxicity against NCI-H460 cell line than Pcb. Z-GP-Pcb was displayed the potency to reduce spermatoxcity in H22-bearing mice. The mechanism may be ascribed to the blockade of dehydrogenation by α-glycerolphosphate dehydrogenase. This candidate was further proved equal antitumor activity to Pcb. However, the introduction of Z-GP scaffold decreased myelosuppression. All the evidences support that Z-GP-Pcb is a better antitumor agent than Pcb.

Indirect oxidation of the antitumor agent procarbazine by tyrosinase--possible application in designing anti-melanoma prodrugs.

The interaction of tyrosinase with the anticancer drug procarbazine has been investigated. In the presence of the enzyme alone no oxidation of this dialkylhydrazine above the background level was observed. However, when phenolic substrates (4-tert-butylcatechol or N-acetyl-l-tyrosine) were included in the reaction mixture, procarbazine was rapidly degraded. Oxygen consumption measurements showed that in a mixture both the phenolic substrate and the drug were oxidized. The major product of procarbazine degradation was isolated and identified as azoprocarbazine, the first active metabolite of this drug detected in previous in vivo and in vitro studies. This indirect oxidation of the hydrazine group in this anticancer agent indicates possible application of a hydrazine linker in construction of tyrosinase-activated anti-melanoma prodrugs.

Evaluation of the dysmorphogenic effects of procarbazine, benzylazoxyprocarbazine, and methylazoxyprocarbazine in whole embryo culture.

Serum from procarbazine (PCZ)-treated rats is dysmorphogenic to rat embryos cultured in vitro, but PCZ is not effective when added directly to culture medium, even with an exogenous metabolizing system. Methylazoxyprocarbazine (MPCZ) is a metabolite which we have identified by HPLC in the dysmorphogenic serum of PCZ-treated rats. PCZ, MPCZ, and benzylazoxyprocarbazine (BPCZ, an isomer of MPCZ) were tested in rat whole embryo culture to determine their effects on embryo development. The parent compound, PCZ, produced no effect on embryo growth or development at concentrations up to 200 micrograms/ml. MPCZ proved to be the most potent of the agents tested. There was significant embryo lethality at concentrations of > or = 10 micrograms/ml while 25 micrograms/ml had significantly reduced embryonic developmental score (DEVS), and 35 micrograms/ml reduced DEVS, head length, and somite number. There was 89% embryo lethality at the 50 micrograms/ml exposure level. At concentrations > 5 micrograms/ml, there were significant increases in anomalies, primarily, failure of neural tube closure, erratic neural seam, and microcephaly. In contrast, BPCZ produced embryo lethality and reductions in DEVS only at 100 micrograms/ml. These data suggest that MPCZ, which has been identified in PCZ-treated rat serum, may be the proximate dysmorphogenic metabolite of PCZ.

A structural modification study of procarbazine.

Eight analogues of the antineoplastic compound procarbazine were prepared by varying one portion of the molecule, keeping either the methylhydrazinomethyl or the N-(1-methylethyl)benzamido portion of procarbazine intact. Preliminary screening results indicated that none of the analogues tested in leukemias L1210 and P388 were as active as the original compound.

Potential antitumor agents: procarbazine analogs and other methylhydrazine derivatives.

With the objective of developing new antitumor agents, two groups of hydrazine compounds, having structural features in common with the antitumor agents procarbazine and 1-acetyl-2-picolinoylhydrazine, were synthesized. The L-1210 leukemia system was used to evaluate compounds of both groups. The aliphatic procarbazines also were screened for antitumor activity as bis(benzyloxycarbonyl) derivatives and as derivatives having a phthalazine nucleus. No L-1210 antitumor activity was exhibited by these compounds.