SYNTHESIS OF CHOLANE AND LANOSTANE DERIVATIVES

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SYNTHESIS OF CHOLANE AND LANOSTANE DERIVATIVES CHOLANE AND LANOSTANE DERIVATIVES: ANTIMICROBIAL EVALUATION Francesca Catenia, Marina Zacchignaa, Giuseppe Procidaa, Jelena Zilica, Angelina Cordoneb, Anna Zanfardinob, Mario Varcamontib aDepartment of Chemical and Pharmaceutical Science, University of Trieste, P.zle Europa 1, 34127 Trieste, Italy bDepartment of Biology, University of Naples Federico II, Complesso Universitario di Monte S. Angelo, Via Cinthia-Edificio 7, 80126 Napoli, Italy INTRODUCTION Bile acids such as lithocholic acid (LCA) and ursodeoxycholic acid (UDCA) (Scheme 1) have been considered quite useful as starting points for a rich and different set of medicinal chemistry activities.[1] The literature describes a large amount of pharmacological applications for bile acids derivatives, in particular antimicrobial, antifungal and antitumor. Besides, the discovery of bioactive ingredients from plants and fungi is always the main target in medicinal chemistry. The lanostane-type triterpenoid 3-hydroxylanosta-8,24-diene-21-oic acid (Trametenolic acid, TMA) (Scheme 2) was the main bioactive component of Gloeophyllum odoratum[2], which was reported to possess widely bioactivities, including tumor cell anti-proliferation effects (for example, human HL-60 leukemia, human KB epidermoid carcinoma, murine L1210 leukemia cells, Caski, HT-3, T-24, etc.), inhibition of enzyme activity (human thrombin, bovine trypsin and so on). Nevertheless, trametenolic acid was scarcely investigated as antimicrobial agent. A new series of lithocholic, ursodeoxycholic and lanostane acid derivatives were synthesized through modification at the oxygenated carbon C-3 and/or C-7 and at the carboxyl carbon C-24 or C-21. R. Sharma, A. Long, J. Gilmer, Current Med. Chem. 2011, 18, 4029-4052. 2. F. Cateni, V. Lucchini, M. Anderluh, P. Martinuzzi, M. Zacchigna, A. Piltaver, B. Doljak, Letters in Drug Design & Discovery 2010, 7, 521-527. . RESULTS The aim of the present study is to obtain a new series of derivatives bearing a guanidine moiety in their side chain through modification at the carboxyl carbon C-24 or C-21 and an acetoxy group at the oxygenated carbon C-3 and/or C-7. The activity of bile acids, trametenolic acid and derivatives was evaluated against the growth of S. aureus, B. subtilis and M. smegmatis. The derivative 3-hydroxy-23-guanidino-5-cholane (6) showed the best activity, with MIC values of 12.5 µM against S. aureus, 5 µM against B. subtilis and 50 µM against M. smegmatis. The cytotoxic activity of bile acids, trametenolic acid and derivatives was also evaluated against HT-29 cell line. SYNTHESIS OF CHOLANE AND LANOSTANE DERIVATIVES Scheme 2 Scheme 1 Scheme 1: Reagents and conditions: (a) Ac2O/pyridine, DMAP, rt, 24 h, 96% (2), 78% (2a); (b) NEt3, DPPA, Toluene, 150°C, reflux, 3h; (c) NaOTMS/THF 1M, 0°C, 1h, 64% (3), 66% (3a); (d) NEt3, AgNO3/CH2Cl2, N,N'-Di-Boc-S-methylisothiourea, 40% (4), 41% (4a); (e) TFA/CH2Cl2, 86% (5), 89% (5a); (f) NaOH/MeOH, 150°C, 1h; (g) TFA/CH2Cl2, 82% (6), 76% (6a). Scheme 2:Reagents and conditions: (a) Ac2O/pyridine, DMAP, rt, 24 h, 87%; (b) NEt3, DPPA, Toluene, 150ºC, reflux, 3h; (c) NaOTMS/THF 1M, 0°C, 1h, 67%; (d) NEt3, AgNO3/CH2Cl2, N,N'-Di-Boc-S-methylisothiourea, 44%; (e) TFA/CH2Cl2, 87%; (f) NaOH/MeOH, 150°C, 1h; (g) TFA/CH2Cl2, 87%. IN VITRO STUDY Table 1: Values of the minimal inhibitory concentration (MIC) of the synthesized compounds. Each value is the highest of three replicates. Compounds Bacterial strains MIC [µM] Bacterial strains MIC [µg/mL] S. aureus ATCC 6538P Bacillus subtilis PY79 Mycobacterium smegmatis mc2 155 1 > 100 25 > 150 > 37 9.5 > 55.5 1a 100 > 39 39 > 59 5 10 150 4.5 64.5 5a 20 50 9 22.5 6 12.5 2 6a 4 8 > 48 > 72 12 n.d. 13 > 46 46 > 76 Figure 1: MTT assay. Effect of the different compounds on HT29 cells survival after 24 h of treatment, at different concentrations from 0 to 50 µM. Cell cytotoxicity determined by MTT assay is expressed as percentage of cell viability and indicated as mean ± SD (n=3), P<0.05. ANOVA test.