Small-molecule based delivery systems for alkylating antineoplastic compounds.
Alkylating agents are a major class of anticancer drugs for the treatment of various cancers including hematological malignancies. Targeting alkylating moieties to DNA by attachment of a DNA minor groove binding carrier such as distamycin, netropsin, or Hoechst 33252 reduces the loss of active drug due to reaction with other cell components and makes it possible to direct the alkylation both sequence specifically and regiospecifically. We reported the synthesis and structure-activity studies of amidine analogues of alkylating antineoplastic compounds, which appeared to be a new class of cytotoxic minor groove binders and topoisomerase II inhibitors. Another approach to overcome the toxicity of alkylating agents to normal tissue is to construct a prodrug with lower hydrophobicity and cytotoxicity but is preferentially activated in cancer cells. Overexpression of prolidase in some neoplastic cells suggests that the proline analogue of alkylating agents may serve as a prolidase convertible prodrugs. We have compared several aspects of pharmacological actions of proline analogues of chlorambucil and melphalan in breast cancer cells. The results suggest that prolidase could serve as a target enzyme for the selective action of anticancer agents.
D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry; D001562:Benzimidazoles / Q000138:chemical synthesis; D002699:Chlorambucil / Q000031:analogs & derivatives; D004247:DNA / Q000378:metabolism; D004150:Dipeptidases / Q000378:metabolism; D004214:Distamycins / Q000138:chemical synthesis; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D008558:Melphalan / Q000031:analogs & derivatives; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D004214:Distamycins; D004791:Enzyme Inhibitors; D011355:Prodrugs; D059005:Topoisomerase II Inhibitors; D002699:Chlorambucil; C030000:stallimycin; D004247:DNA; D004150:Dipeptidases; C022449:proline dipeptidase; D008558:Melphalan