Subject(s)
Folic Acid Antagonists , Animals , Folic Acid Antagonists/therapeutic use , Folic Acid Antagonists/toxicity , Lethal Dose 50 , Leukemia L1210/drug therapy , Methotrexate/analogs & derivatives , Methotrexate/therapeutic use , Methotrexate/toxicity , Rats , Rats, Inbred Strains , Structure-Activity RelationshipABSTRACT
Quantitative structure-activity relationships for the carcinogenicity and mutagenicity (against Salmonella typhimurium his- TA98, TA100 and TA1537 strains) of 43 structurally related heterocyclic compounds were formulated. The compounds investigated belong to the following two series of congeners : (a) benzo(thio)-pyranoquinolines and (b) benzo(thio)pyranoindoles. Their biologic activities were correlated with the following parameters : (a) the minimal topological difference (describing the fit of the considered molecules with a possible receptor, enzyme or DNA) and (b) the lipophilicity constants. The computed regression equations suggest that the structural requirements for carcinogenicity are different from those responsible for mutagenicity in the Ames test.
Subject(s)
Carcinogens , Heterocyclic Compounds/toxicity , Mutagens , Salmonella typhimurium/genetics , Structure-Activity RelationshipABSTRACT
A series of 31 aromatic nitrogen mustards was treated by means of the Minimal Tropological Difference (MTD)-receptor site mapping procedure by respect to toxicity (LD50) and efficacy (TGI%) against Jensen sarcoma. The correlation equations obtained for the two cases are: (Formula: see text), The low correlation coefficients indicate a not too high dependence upon steric factors of TGI% and LD50. However these results suggested that: a) the ortho-substitution represents a favorable event for both toxicity and antitumor effectiveness (j = 1 and 18 being good vertices in both corresponding hypermolecules), b) despite this effect, the steric features involved in these two biologic parameters seems to be different.
Subject(s)
Antineoplastic Agents/pharmacology , Neoplasms, Experimental/drug therapy , Nitrogen Mustard Compounds/pharmacology , Animals , Antineoplastic Agents/metabolism , Binding Sites , Rats , Structure-Activity RelationshipABSTRACT
Quantitative structure--activity relationships have been fomulated for 27 aromatic nitrogen mustards derived from benzoic acids (9 monosubstituted and 18 disubstituted derivatives). Their toxicity (LD50) and antitumor activity against Jensen sarcoma were correlated with hydrolysis rate (log k66) lipophilicity constants (pi) and steric parameters (MDT). The chemical reactivity of the nitrogen mustard moiety (expressed as log k66) seems to be of main importance in determining the biological properties of these derivatives. The favorable effect of ortho-substitution was pointed out. Generally these results are in good agreement with those obtained by HANSCH et al. [7] on a different series of nitrogen mustards.
