mannich-bases and Mouth-Neoplasms

Mannich bases of thymol were synthesized. The aminomethylation reaction was realised in the ortho position of the phenol for compounds 2 (dipropylamine), 3 (benzylamine), and 4 (dibenzylamine) while it was from para position for 1 (dimethylamine), 5 (piperidine), 6 (morpholine) and 7 (N-methylpiperazine). The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects of the compounds were asssessed against hCA I and hCA II. All compounds moderately inhibited hCA I and hCA II. The cytotoxicity of the compounds against four human oral squamous cell carcinoma cell lines were compared those against three normal oral cells. Tumor specificity values were about 2 or slightly more for the compounds 2, 3, 4, 5 and 6. Compound 2 showed cytostatic activity against OSCC cell lines at 16 to 32-fold lower concentrations as compared with normal cells. This suggests that compound 2 can be considered as cytotoxicity enhancing drug candidate for further investigations.

Topics: Antineoplastic Agents; Carbon-13 Magnetic Resonance Spectroscopy; Carbonic Anhydrase Inhibitors; Carcinoma, Squamous Cell; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Mannich Bases; Mouth Neoplasms; Proton Magnetic Resonance Spectroscopy; Spectrometry, Mass, Electrospray Ionization; Thymol

Phenolic bis Mannich bases having the chemical structure of 1-[3,5-bis-aminomethyl-4-hydroxyphenyl]-3-(4-halogenophenyl)-2-propen-1-ones (1a-c, 2a-c, 3a-c) were synthesized (Numbers 1, 2, and 3 represent fluorine, chlorine, and bromine bearing compounds, respectively, while a, b, and c letters represent the compounds having piperidine, morpholine, and N-methyl piperazine) and their cytotoxic and carbonic anhydrase (CA, EC 4.2.1.1) enzyme inhibitory effects were evaluated. Lead compounds should possess both marked cytotoxic potencies and selective toxicity for tumors. To reflect this potency, PSE values of the compounds were calculated. According to PSE values, the compounds 2b and 3b may serve as lead molecules for further anticancer drug candidate developments. Although the compounds showed a low inhibition potency toward hCA I (25-43%) and hCA II (6-25%) isoforms at 10 μM concentration of inhibitor, the compounds were more selective (1.5-5.2 times) toward hCA I isoenzyme. It seems that the compounds need molecular modifications for the development of better CA inhibitors.

Topics: Antineoplastic Agents; Carbonic Anhydrase I; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Carcinoma, Squamous Cell; Cell Line; Cell Proliferation; Chalcones; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Halogens; Humans; Isoenzymes; Mannich Bases; Molecular Structure; Mouth Neoplasms; Phenols; Solubility; Structure-Activity Relationship