Abstract
Incorporation of carbobenzoxy-glycylprolyl (Z-GP) to either α or β 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.
Keywords:
FAPα; Myelosuppression; Procarbazine; Spermatoxicity; Targeted anti-cancer.
Copyright © 2018 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Antineoplastic Agents / toxicity
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Blood Cell Count
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Blood Cells / drug effects*
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Blood Platelets / drug effects
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Cell Line, Tumor
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Dipeptides / chemical synthesis
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Dipeptides / pharmacology
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Dipeptides / therapeutic use*
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Dipeptides / toxicity
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Drug Design
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Endopeptidases
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Erythrocytes / drug effects
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Gelatinases / metabolism
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Humans
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Hydrolysis
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Leukocytes / drug effects
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Male
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Membrane Proteins / metabolism
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Mice
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Organ Size
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Procarbazine / chemical synthesis
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Procarbazine / pharmacology
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Procarbazine / therapeutic use*
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Procarbazine / toxicity
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Prodrugs / chemical synthesis
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Prodrugs / pharmacology
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Prodrugs / therapeutic use*
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Prodrugs / toxicity
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Serine Endopeptidases / metabolism
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Sperm Count
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Spermatozoa / drug effects*
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Testis / drug effects
Substances
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Antineoplastic Agents
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Dipeptides
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Membrane Proteins
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Prodrugs
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Procarbazine
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Endopeptidases
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Serine Endopeptidases
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fibroblast activation protein alpha
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Gelatinases