Bis-naphthylureas and related compounds: synthesis, chemical properties, DNA affinity and antineoplastic activity.

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.

Human DNA topoisomerase I poisoning activity of bis-1-aminomethylnaphtalenes. A correlation with their cytotoxic activity.

Symmetrical bis-1-aminmoethylnaphtalenes, a group of compounds that demonstrated cytotoxicity towards human tumor cell lines, showed human topoisomerase I poisoning activity. The compounds tested were: N,N'-bis-1-naphthylmethyl-1,6-hexanediamine (1a), N,N'-bis-1-naphthylmethyl-1,8-octanediamine (1b), N,N'-bis-1-naphthylmethyl-1,12-dodecanediamine (1c), N,N'-bis-1-naphthylmethyl-4,4-bipiperidine (2) and N-(1-naphthylmethyl)-N'-dimethyl-1,3-diaminepropane dichlorhydrate (3). All showed human topoisomerase I inhibition by producing protein-linked DNA breaks. The most active were 1a, 1b, 1c with a percentage stimulation of DNA cleavage of 75, 84 and 70% at 100 micrograms/ml, respectively. Compounds 2 and 3 were moderately active as poisons of topoisomerase I activity, the former showing 58% stimulation of DNA cleavage at 100 micrograms/ml and the latter a 24% stimulation. The correlation observed between topoisomerase I poisoning and in vitro cytotoxic activity suggests that this could be a possible mechanism for the cytotoxicity observed in tumor cell lines.

Diarylsemicarbazones: synthesis, antineoplastic activity and topoisomerase I inhibition assay.

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.

Synthesis, DNA interaction and antineoplastic activity of semicarbazone derivatives.

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.

DNA interaction and electrochemical properties of bis-1-aminomethylnaphthalenes and related compounds. A correlation with their antineoplastic activity.

Bis-1-aminomethylnaphthalenes constitute a new type of molecule with antineoplastic activity. As a first approach to determine the action mechanism, the interaction degree of these compounds and some less active analogous, with calf thymus DNA, by UV spectrophotometry, and the redox performance by cyclic voltammetry was correlated with their activity on neoplastic cell lines. It suggests that the most active members interact closely with DNA but do not show any redox process at biological potentials.