Evaluation of the cytotoxicity of some mono-mannich bases and their corresponding azine derivatives against androgen-independent prostate cancer cells.
Mono-Mannich bases derived from acetophenones, 1-aryl-3-amino- 1 -propanone hydrochlorides (Igl-Ig4), and their corresponding azine derivatives, N, N'-bis(3-amino-l-aryl-propylidene) hydrazine dihydrochlorides (DI-D4), were designed and synthesized as cellular thiol alkylating agents. The aryl portion was replaced by a phenyl group in Ig1, Ig2, Ig3, D1, D2, and D3, and by a p-hydroxyphenyl group in Ig4 and D4. The amine side chain was replaced by a dimethylamine group in Igl, D1, Ig4 and D4, by a piperidine group in Ig2 and D2, and by a morpholine group in Ig3 and D3. The cytotoxic activity of the compounds was tested against the androgen-independent prostate cancer cell line PC-3. The relationship between cytotoxicity and pKa value of the amine group and partition coefficients of the compounds was also investigated. Azine derivative D4 was found to be the most potent among all the compounds tested and the cytotoxicity increased 1.73 fold compared with the mono-Mannich base Ig4 in PC-3 cells. On the other hand, conversion of mono-Mannich bases Igl-Ig3 to their corresponding azine derivatives DI-D3 decreased the cytotoxicity considerably. Substitution of the hydroxyl group at the para position of the aromatic ring in azine derivative D4 increased the cytotoxicity, and a rational explanation in this regard is described in length. The results emerged from this investigation guide the future expansion of these series of compounds.
Gul
Halise Inci
HI
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey. incigul1967@yahoo.com
Das
Umashankar
U
Pandit
Bulbul
B
Li
Pui-Kai
PK
D000728:Androgens / Q000502:physiology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008352:Mannich Bases / Q000138:chemical synthesis / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D021281:Quantitative Structure-Activity Relationship; D013056:Spectrophotometry, Ultraviolet
D000728:Androgens; D000970:Antineoplastic Agents; D006834:Hydrazines; D008352:Mannich Bases