ABSTRACT
The biological activities of the naphthoquinones lapachol, extracted from trees of the genus Tabebuia and its cyclization products alpha and beta-lapachone, have been intensively studied. Giving continuity to the research about new derivatives obtained from the reaction of these naphthoquinones with amino-containing reagents, a series of arylhydrazones of alpha-lapachone was synthesized and their antineoplastic activity was evaluated. This new structure is based on the great electrophilicity of 1,4-quinoidal carbonyl groups towards reagents containing nitrogen as nucleophilic centers, such as arylhydrazines. The products were assayed by the National Cancer Institute (NCI, USA) and their binding to DNA, redox properties and QSAR studies were also determined.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Hydrazones/chemical synthesis , Hydrazones/pharmacology , Naphthoquinones/chemical synthesis , Naphthoquinones/pharmacology , Algorithms , Cell Line, Tumor , Chemical Phenomena , Chemistry, Physical , DNA/chemistry , Drug Screening Assays, Antitumor , Electrochemistry , Humans , Models, Molecular , Quantitative Structure-Activity RelationshipABSTRACT
A series of bis-naphthalene derivatives in which these moieties are linked by a symmetric bis-urea functionalized chain or by an asymmetric amide and urea or amino and urea functionalized chain, were synthesized. The tentative synthesis of other types of related compounds did not give the products expected. The compounds were assayed as antineoplastics on human tumor cell lines at the National Cancer Institute (USA). Bis-urea derivatives were active on lung, colon, renal and CNS tumor cell lines. The degree of affinity of these compounds to DNA was also studied, showing low affinity.
Subject(s)
Antineoplastic Agents/pharmacology , DNA/drug effects , Intercalating Agents/pharmacology , Naphthalenes/chemical synthesis , Urea/analogs & derivatives , Urea/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , DNA/chemistry , Drug Screening Assays, Antitumor , Humans , Intercalating Agents/chemical synthesis , Intercalating Agents/chemistry , Naphthalenes/chemistry , Naphthalenes/pharmacology , Spectrophotometry, Ultraviolet , Tumor Cells, Cultured , Urea/chemistry , Urea/pharmacologyABSTRACT
A series of diarylsemicarbazones was synthesized and tested against human neoplastic cell lines. The more active members have a l-naphthyl ring at the carbamidic nitrogen, and chloro, dimethylamino or nitro group substituents at the benzylidene moiety. None of these showed affinity to DNA. One of the more active compounds was tested as a topoisomerase I inhibitor and showed a potent effect. SAR studies demonstrated linear correlation between lypophilicity and activity on the most sensitive lines and a definite conformational shape for antineoplastic action.
Subject(s)
Antineoplastic Agents/chemical synthesis , Azo Compounds/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Topoisomerase I Inhibitors , Antineoplastic Agents/pharmacology , Azo Compounds/pharmacology , DNA/metabolism , Drug Screening Assays, Antitumor , Electrochemistry , Enzyme Inhibitors/pharmacology , Humans , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A number of antineoplastic agents including procarbazine and bisantrene derive from hydrazine, but so far none have been developed from semicarbazide. In order to assay active minimal structures, thirteen new compounds were prepared by replacing hydrogen atoms in semicarbazone amine group by alkylamine moieties, employing an improved procedure. DNA binding was evaluated by treatment of a drug solution with DNA-cellulose complex and further measurement of remaining drug by UV spectroscopy and the affinity observed to range from medium to weak. On testing these compounds against human neoplastic cell lines, only a nitroderivative proved active on CNS and Breast cell lines at 10(-4) M. This member was studied by cyclic voltammetry.
