Anticancer activity of cytokinins: structure-activity relationship studies

Jiří Voller

Doctoral thesis

Abstract:

A study of the relationship between the chemical structure of cytokinins and their cytotoxic effects against a panel of human cancer cell lines with diverse histopathological origins is presented. Test compounds included almost all known natural cytokinins (N = 42) and two groups of novel synthetic analogues: derivatives of N6-benzyladenosine with diverse substitutions on the benzyl ring (N = 48) and their analogues where the ribose moiety is replaced by a tetrahydropyran-2-yl or tetrahydrofuran-2-yl group (N = 34). Strong cytotoxic activity was limited to certain cytokinin ribosides and their corresponding ribotides. The anticancer activity of aromatic cytokinin ribosides can be improved by fluorination or ortho- hydroxylation of the benzyl ring. The potent anticancer activity of the natural cytokinin ortho-topolin riboside (median GI50 = 0.65 ?M) was confirmed using NCI60. Its activity pattern was distinctly different from those of standard anticancer drugs, suggesting that it has a unique mechanism of action. In comparison with standard drugs, ortho-topolin riboside showed exceptional cytotoxic activity against NCI60 cell lines with a mutated p53 tumour suppressor gene. Ortho-topolin riboside also exhibited significant anticancer activity against several tumour models in in vivo hollow fibre assays

Abstract:

A study of the relationship between the chemical structure of cytokinins and their cytotoxic effects against a panel of human cancer cell lines with diverse histopathological origins is presented. Test compounds included almost all known natural cytokinins (N = 42) and two groups of novel synthetic analogues: derivatives of N6-benzyladenosine with diverse substitutions on the benzyl ring (N = 48) and their analogues where the ribose moiety is replaced by a tetrahydropyran-2-yl or tetrahydrofuran-2-yl group (N = 34). Strong cytotoxic activity was limited to certain cytokinin ribosides and their corresponding ribotides. The anticancer activity of aromatic cytokinin ribosides can be improved by fluorination or ortho- hydroxylation of the benzyl ring. The potent anticancer activity of the natural cytokinin ortho-topolin riboside (median GI50 = 0.65 ?M) was confirmed using NCI60. Its activity pattern was distinctly different from those of standard anticancer drugs, suggesting that it has a unique mechanism of action. In comparison with standard drugs, ortho-topolin riboside showed exceptional cytotoxic activity against NCI60 cell lines with a mutated p53 tumour suppressor gene. Ortho-topolin riboside also exhibited significant anticancer activity against several tumour models in in vivo hollow fibre assays

Keywords

SAR, cytokinins, cancer, ortho-topolin riboside, NCI60

Keywords

SAR, cytokinins, cancer, ortho-topolin riboside, NCI60

Language used: English

Date on which the thesis was submitted / produced: 24. 6. 2010

Thesis defence

• Date of defence: 24. 6. 2010
• Supervisor: Miroslav Strnad
• Reader: Jan Kovařík, Enzo Santaniello, Petr Mlejnek

Univerzita Palackého

Přírodovědecká fakulta

Doctoral programme / field:
Biologie / Botanika