Antileukemic and cytogenetic effects of modified and non-modified esteric steroidal derivatives of 4-methyl-3-bis(2-chloroethyl)amino benzoic acid (4-Me-CABA).
The increase of the damaging effects on specific DNA sequences and the reduction of the subsequent toxicity of nitrogen mustards has been achieved by their chemical conjugation with modified steroids through an esteric bond. In an attempt to study the structure-activity relationships of these compounds, we synthesized eight steroidal esters of 4-methyl-3-bis(2-chloroethyl)aminobenzoic acid (4-Me-CABA). The anti-leukemic and cytogenetic effects of the parent alkylating agent were compared with those produced by the steroidal compounds, in vivo against leukemias P388 and L1210 and in vitro for induction of Sister Chromatid Exchanges (SCE) and on proliferation rate indices (PRI). The results demonstrate that the existence of the NH-CO group, either as an endocyclic lactamic or as an out of the ring amidic one but at axial conformation, at the steroid-carrier moiety is necessary for the expression of the antileukemic activity. The synthetic route for the preparation of the steroidal esters and their physicochemical data are also reported.
Fousteris
Manolis A
MA
School of Health Sciences, Department of Pharmacy, University of Patras, Rion, Greece.
Koutsourea
Anna I
AI
Arsenou
Evagelia S
ES
Papageorgiou
Athanasios
A
Mourelato
Dionisis
D
Nikolaropoulos
Sotiris S
SS
D010129:4-Aminobenzoic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy*; D007941:Leukemia P388 / Q000188:drug therapy*; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D013329:Structure-Activity Relationship; D062366:para-Aminobenzoates
C465013:4-methyl-3-bis(2-chloroethyl)aminobenzoic acid; D000970:Antineoplastic Agents; D062366:para-Aminobenzoates; D010129:4-Aminobenzoic Acid