JUNI EKOWATI, 090810031 D (2012) SINTESIS TURUNAN p-METOKSISINAMOILTIOUREA DARI ETIL p-METOKSISINAMAT ISOLAT Kaempferia galanga DALAM USAHA MENINGKATKAN AKTIVITAS KEMOPREVENTIF KANKER MELALUI HAMBATAN CYCLOOXYGENASE-2. Disertasi thesis, UNIVERSITAS AIRLANGGA.

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Abstract

Inhibition of cyclooxygenase-2 (COX-2) is promising to block the progression of cancer. COX-2 could catalyzes production of PGE 2 metabolism of arachidonic acid, which is triggering progressive growth of neoplasm, angiogenesis and metastases. Utilization of COX-2 inhibitor, particularly coxibs in the long term, will give adverse effects such as on cardiovascular. This finding encourages continuously research syntheses of COX-2 inhibitors as chemopreventive cancer. Ethyl p-methoxycinnamate (EPMS), major ingredient of Kaempferia galanga rhizome, has been reported as analgesic – anti inflammatory agent repressed cyclo-oxygenase, and inhibits tumor cell proliferation of mouse epidermis. So, it is used as lead compound to search the new compound as chemopreventive agent against cancer through COX-2 inhibition. In silico study on COX-2 (pdb. 1CX2) by Molegro program was used to design derivatives of EPMS as COX-2 inhibitor. Among those derivatives of EPMS, thiourea derivatives from EPMS(namely (N-(phenyl) -N’-(p-me-thoxycinnamoyl)thiourea,N-(p-methylphenyl)-N’-(p-methoxycinnamoyl)thiourea, N-(p-methoxyphenyl)-N’-(p-methoxy- cinnamoyl)thiourea, N-(p-chlorophenyl)-N’-(p-methoxycinnamoyl)thiourea and N-(p-sul-phonamidophenyl)-N’-(p-methoxycinnamoyl)thiourea showed the lowest MolDockScore. Those thiourea derivatives were synthesized by hydrolysis EPMS to produce APMS, conversion this acid to acyl halide, substitution and addition of acyl halide with ammonium thiocyanate and commercial amines, then were confirmed by UV-Vis, FTIR, 1H-NMR, 13C-NMR and HRMS spectroscopic methods. Their activities were tested in vivo using mice model at dosage 20, 40 and 80 mg/kg, given daily for thirty days. Celecoxib was used as positive control. Carcinogenesis was induced by 0.3% benzo(a)pyrene injected sub cutaneously on intra scapular area of mice, which was given five times, once every two days. Inhibition of COX-2 expression of derivatives p-me- thoxycinnamoylthiourea on cancer cell were tested by immunohistochemistry using Avi-din Biotin Method. The results showed that chemopreventive activity of all syn-thesized compounds on carcinogenesis process through inhibition of COX-2 expression better than EPMS. N-(p-sulphonamidophenyl)-N’-(p-methoxycinnamoyl)thiourea showed the stro-ngest activity among those derivatives. Structure activity relationship of p-methoxycinnamoylthiourea derivatives as cancer chemoprevention indicated that the steric effect of the addition of one more phenyl moiety and the electronic effects of electronegative atom attached to the para position of that phenyl moiety play the important role in cancer chemoprevention activity through COX-2 inhibition. This is due to the similarity of the spatial structure between celecoxib and those p-methoxycinnamoylthiourea derivatives, so those p-methoxy-cinnamoylthiourea derivatives can be more selective into COX-2 cavity than that COX-1.

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