IQUIFIB   02644
INSTITUTO DE QUIMICA Y FISICOQUIMICA BIOLOGICAS "PROF. ALEJANDRO C. PALADINI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
β-Lactams and their potential use as anticancer drugs
Autor/es:
CORNIER P.G.; BOGGIÁN DORA B.; CARDENAS MARIANO; ROGUIN, LEONOR P.
Lugar:
Córdoba, Córdoba, Argentina.
Reunión:
Congreso; 1ª Reunión Internacional de Ciencias Farmacéuticas (RICiFa); 2010
Institución organizadora:
Universidad Nacional de Córdoba
Resumen:
β-LACTAMS AND THEIR POTENTIAL USE AS ANTICANCER DRUGS   Cornier, P.G.; # Boggián, D.B.;[i] # Cárdenas, M.G.;§ Roguin, L.P. §   # IQUIR (CONICET-UNR), FBIOyF UNR, Suipacha 531, 2000 Rosario § Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Junín 956, 1113 BsAs   Introduction Recent studies have demonstrated that some b-lactam antibiotics posses cytotoxic activity against a group of tumor cells.1a,b For this reason, and considering that b-lactam antibiotics have been used for many years to treat bacterial infections with limited or no toxicity, we evaluated the antiproliferative action of a 2b-(heterocyclyl)thiomethyl penicillins library.   Materials and methods 6b-aminopenicillanic acid (6-APA) obtained by deacylation of natural penicillins, have been used as starting material. We modified different positions of the 6-APA core, introducing several substituents, many of them known pharmacophores.To carry out these transformations, we have used homogeneous and solid-phase synthesis strategies.   Results The antiproliferative activity of 25 synthetic penicillin derivatives was tested in vitro. Herein we report the results related to the most relevant group of compounds. Initially we employed a 20 μM concentration and two human tumor cell lines (cervix HeLa adenocarcinoma; breast MCF-7) and two murine cell lines (B16-F0 melanoma; LM3 mammary adenocarcinoma). Additionally, epithelial cells derived from normal mammary gland (NMuMG) were used as controls. The antiproliferative activities, expressed as IC50 values, are summarized in Table 1. Among the tested compounds, 1a, 1b and 1d did not exhibit a considerable cytotoxic effect toward control NMuMG cells. In general terms, in tumor cell lines, compounds have shown the follow order of potency: 1f~1c > 1a > 1e~1g > 1b > 1d. Penicillin 1a, showed the greatest selectivity, being approximately eight times more active in HeLa cells than in NMuMG cells.   Conclusions From the analysis of this penicillin library we can see that 2β-(benzothiazo-2-yl)thiomethyl group (1a and 1e) and 2β-[(4,5-diphenyl-oxazol-2-yl)thio]methyl group (1b, 1c, 1f, and 1g) are important to achieve activity in the compounds tested, while no  significant change from varying the ester groups in position 3 of the penam nucleus. These preliminary results will help us to design and synthesize new analogues in order to obtain better activity and selectivity in antitumor therapy.     Table 1   Compound   IC50  values (μM)a   HeLa MCF-7 LM3 B16 NMuMG 3-(Benzothiazol-2-ylsulfanylmethyl)-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid benzyl ester (1a)   11 ± 1   ND   ND   ND   >80 3-(4,5-Diphenyl-4,5-dihydro-oxazol-2-ylsulfanylmethyl)-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid benzyl ester (1b)   20 ± 3   ND   ND   ND   >80   3-(4,5-Diphenyl-4,5-dihydro-oxazol-2-ylsulfanylmethyl)-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid methyl ester (1c)   8 ± 1   20   20 ± 1   ND   40 3-(4,5-Dihydro-thiazol-2-ylsulfanylmethyl)-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid benzyl ester (1d )   ND   ND   23 ± 4   ND   >80 3-(Benzooxazol-2-ylsulfanylmethyl)-6,6-dibromo-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid methyl ester (1e) 14±4 ND ND ND 13±4 6,6-Dibromo-3-(4,5-diphenyl-4,5-dihydro-oxazol-2-ylsulfanylmethyl)-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid methyl ester (1f) 7±2 18±1 14±3 11±3 31±1 6-Chloro-3-(4,5-diphenyl-4,5-dihydro-oxazol-2-ylsulfanylmethyl)-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid methyl ester  (1g ) 13±4 ND 27±7 ND 32±8   aThe molar concentration of a drug that is required for 50% inhibition, determined from dose-response curves. Results represent the average of, at least, three experiments. ND: not determined, corresponding to compounds that inhibit proliferation in less than 50% at 20 μM.       Acknowledgements: CONICET, ANPCYT and Universidad Nacional de Rosario.         References 1-a- Smith, D.M., Kazi, A., Long, B:, Heldrech, E: Biochem Pharmacol. 2002, 61, 1348.     b- Kazi, A., Hill, R., Long, T. E., Kuhn, D.J., Turos, E. Biochem Pharmacol. 2004, 67, 365.                         [i] Boggian, Dora Bernarda. Tel +54 341  4370477; e-mail: boggian@iquir-conicet.gov.ar