piperidines and 3-6-bis(5-chloro-2-piperidyl)-2-5-piperazinedione

Nitrogen mustards are an important class of bifunctional alkylating agents routinely used in chemotherapy. They react with DNA as electrophiles through the formation of highly reactive aziridinium ion intermediates. The antibiotic 593A, with potential antitumor activity, can be considered a naturally occurring piperidine mustard containing a unique 3-chloropiperidine ring. However, the total synthesis of this antibiotic proved to be rather challenging. With the aim of designing simplified analogues of this natural product, we developed an efficient bidirectional synthetic route to bis-3-chloropiperidines joined by flexible, conformationally restricted, or rigid diamine linkers. The key step involves an iodide-catalyzed double cyclization of unsaturated bis-N-chloroamines to simultaneously generate both piperidine rings. Herein we describe the synthesis and subsequent evaluation of a series of novel nitrogen-bridged bis-3-chloropiperidines, enabling the study of the impact of the linker structure on DNA alkylation properties. Our studies reveal that the synthesized compounds possess DNA alkylating abilities and induce strand cleavage, with a strong preference for guanine residues.

Topics: Alkylating Agents; Alkylation; Antineoplastic Agents, Alkylating; Cyclization; DNA Cleavage; Molecular Conformation; Nitrogen Mustard Compounds; Piperazines; Piperidines; Plasmids

Topics: Antibiotics, Antineoplastic; Chromatography, Thin Layer; Fermentation; Piperazines; Piperidines

In order to determine whether piperazinedione used in low doses in combination with cyclophosphamide plus dimethyl-triazeno-imidazole carboxamide (DTIC) produced variable or severe myelosuppression, a Phase I Study was performed in 10 patients who received 16 courses of the three-drug combination. Although mild myelosuppression was consistently observed at doses of 4 mg piperazinedione, 400 mg cyclophosphamide, plus 400 mg DTIC, variable, severe, and prolonged myelosuppression was seen in three of six patients who received a dose of each of the drugs only 25% higher. The only other abnormality observed was nausea and vomiting. This study indicates that low doses of piperazinedione can produce variable and severe myelosuppression when used in combination with other myelosuppressive agents, and that only small increments in dosage may produce marked increases in the degree of myelosuppression. Future combination chemotherapy regimens employing piperazinedione should undergo cautious Phase I toxicity testing to avoid severe depression of blood counts.

Topics: Bone Marrow; Cyclophosphamide; Dacarbazine; Drug Therapy, Combination; Humans; Neoplasms; Piperazines; Piperidines; Triazenes

We sutdied the effect of 3,6-bis(5-chloro-2-piperidinyl)-2,5-piperazinedione (BCP) on various parameters of the replication cycle and cell grwoth on monolayer cultures of Chinese hamster ovary cells. The results indicated that BCP had no effect on the G-S transition or the passage of cells from metaphase to G. However, BCP prolonged S- and G-phases because of its retarding effect on DNA synthetis. BCP was more toxic to S-phase cells than to G or mitotic cells. As with other alkylating agents, chromosome damage due to BCP could be seen only in cells that had undergone DNA replication after exposure to the drug.

Topics: Antineoplastic Agents; Cell Division; Cell Survival; Cells, Cultured; Chromosome Aberrations; DNA Replication; Kinetics; Piperazines; Piperidines

Topics: Alkylating Agents; Animals; Antibiotics, Antineoplastic; Ascites; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Drug Resistance; Leukemia L1210; Leukemia, Experimental; Mercaptopurine; Methotrexate; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Piperazines; Piperidines; Transplantation, Homologous