title: Synthesis and antineoplastic activity of some cyano-, carboxy-, carbomethoxy-, and carbamoylborane adducts of heterocyclic amines.
abstract: Boron analogues of piperidine, piperazine, morpholine, and imidazole proved to be cytotoxic against the growth of murine and human tissue culture cells. Significant activity was demonstrated for single-cell suspensions of L1210 lymphoid leukemia, Tmolt3 lymphoblastic leukemia, and HeLa-S3 cervical carcinoma. Trimethylamine-imidazole carbonyldihydroborane 17 demonstrated activity against solid tumor growth of human colorectal adenocarcinoma, KB nasopharynx, and osteosarcoma. In addition, 4-methylpiperidine-carbomethoxyborane 12, 2-methylimidazole-3-cyanoborane 16, and 1-methylimidazole-3-(N-ethylcarbamoyl)borane 19 were active against the KB nasopharynx growth. Piperidine-cyanoborane 2, piperidine-carboxyborane 4, and 1-methylimidazole-3-(N-ethylcarbamoyl)borane 19 were effective in reducing the growth of osteosarcoma cells. The imidazole derivatives 13-19, as well as 4-methylpiperidine-carboxyborane 11 and carbomethoxyborane 12, demonstrated good activity against lung bronchogenic and glioma growth. In the in vivo studies, N-methylmorpholine-carboxyborane 7,4-phenylpiperidine-carboxyborane 9, 4-phenylpiperidine-carbomethoxyborane 10, 4-methylpiperidine-carboxyborane 11, imidazole cyanoborane 14, and 1-methylimidazole-3-carbomethoxyborane 18 demonstrated the best activity against Lewis Lung growth and P388 lymphocytic leukemia growth in mice. Mode of action studies in L1210 leukemia cells demonstrated that piperidine-carboxyborane 4 and N-methylmorpholine-carboxyborane 7 inhibited DNA synthesis, purine synthesis at PRPP amido transferase and IMP dehydrogenase sites, and thymidine kinase and thymidine diphosphate kinase activities, while lowering d(NTP) pool levels. Also, DNA strand scission was evident after incubation with these drugs.
authors.affiliation: Paul Gross Chemical Laboratory, Chemistry Department, Duke University, Durham, NC 27706.
authors.forename: C K
authors.initials: CK
authors.lastname: Sood
authors.forename: A
authors.initials: A
authors.lastname: Sood
authors.forename: B F
authors.initials: BF
authors.lastname: Spielvogel
authors.forename: J A
authors.initials: JA
authors.lastname: Yousef
authors.forename: B
authors.initials: B
authors.lastname: Burnham
authors.forename: I H
authors.initials: IH
authors.lastname: Hall
mesh_terms: D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D001880:Boranes / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy; D007945:Leukemia, Lymphoid / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D014407:Tumor Cells, Cultured
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D001880:Boranes; D006571:Heterocyclic Compounds