Anticancer activity of natural cytokinins: A structure–activity relationship study

• Published in: Phytochemistry (Oxford) Vol. 71; no. 11; pp. 1350 - 1359
• Main Authors: Voller, Jiří, Zatloukal, Marek, Lenobel, René, Doležal, Karel, Béreš, Tibor, Kryštof, Vladimír, Spíchal, Lukáš, Niemann, Percy, Džubák, Petr, Hajdúch, Marián, Strnad, Miroslav
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2010; Elsevier
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemistry; Adenosine - pharmacology; anticarcinogenic activity; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; benzyladenosine; bioassays; Biochemistry & Molecular Biology; Biological and medical sciences; Cancer; chemical concentration; Chemical constitution; chemical structure; cytokinin nucleotides; cytokinin ribosides; Cytokinins; Cytokinins - analysis; Cytokinins - chemistry; Cytokinins - metabolism; cytotoxicity; Drug Screening Assays, Antitumor; Fundamental and applied biological sciences. Psychology; General pharmacology; Genes, p53 - drug effects; Genes, p53 - genetics; human cell lines; Humans; hydroxylation; in vitro studies; Inhibitory Concentration 50; isopentenyladenosine; Isopentenyladenosine - analogs & derivatives; Isopentenyladenosine - chemistry; Isopentenyladenosine - pharmacology; isoprenoids; kinetin; Kinetin - chemistry; Kinetin - pharmacology; Life Sciences & Biomedicine; Medical sciences; medicinal properties; metabolites; Molecular Structure; National Cancer Institute (U.S.); NCI 60; neoplasms; ortho-Topolin riboside; p53 tumor suppressor gene; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; phytochemicals; Plant Growth Regulators - pharmacology; Plant physiology and development; Plant Sciences; SAR; Science & Technology; Stereoisomerism; Structure-Activity Relationship; structure-activity relationships; United States; zeatin; United States; PBS; DTP; Cytokinins; SAR; NCI 60; ortho-Topolin riboside; Cancer; KINETIN-RIBOSIDE; X CANADENSIS MOENCH; HL-60 CELLS; TUMOR-CELLS; CV ROBUSTA; RIBONUCLEOTIDE REDUCTASE; CORRESPONDING MONONUCLEOTIDES; TOBACCO BY-2 CELLS; NCI; BIOLOGICAL-ACTIVITY; HUMAN CANCER; Antineoplastic agent; Pharmacognosy; Chemical structure; Malignant tumor; Cytokinin; Medicinal plant; Structure activity relation; Plant origin; Tumor cell
• ISSN: 0031-9422; 1873-3700
• DOI: 10.1016/j.phytochem.2010.04.018

This report describes the first systematic structure–activity relationship study of cytokinin anticancer activity against a diverse panel of human cancer cell lines. Analysis of the activity of the most effective cytokinin, ortho-topolin riboside, against NCI 60 cell panel suggests that its mechanism of action differs from that of the standard antineoplastics. The synthesis of new cytokinin nucleotides is also described. Cytokinin ribosides (N 6-substituted adenosine derivatives) have been shown to have anticancer activity both in vitro and in vivo. This study presents the first systematic analysis 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. The results confirm the cytotoxic activity of N 6-isopentenyladenosine, kinetin riboside, and N 6-benzyladenosine and show that the spectrum of cell lines that are sensitive to these compounds and their tissues of origin are wider than previously reported. The first evidence that the hydroxylated aromatic cytokinins ( ortho-, meta-, para-topolin riboside) and the isoprenoid cytokinin cis-zeatin riboside have cytotoxic activities is presented. Most cell lines in the panel showed greatest sensitivity to ortho-topolin riboside (IC 50 = 0.5–11.6 μM). Cytokinin nucleotides, some synthesized for the first time in this study, were usually active in a similar concentration range to the corresponding ribosides. However, cytokinin free bases, 2-methylthio derivatives and both O- and N-glucosides showed little or no toxicity. Overall the study shows that structural requirements for cytotoxic activity of cytokinins against human cancer cell lines differ from the requirements for their activity in plant bioassays. The potent anticancer activity of ortho-topolin riboside (GI 50 = 0.07–84.60 μM, 1st quartile = 0.33 μM, median = 0.65 μM, 3rd quartile = 1.94 μM) was confirmed using NCI 60, a standard panel of 59 cell lines, originating from nine different tissues. Further, the activity pattern of oTR was distinctly different from those of standard anticancer drugs, suggesting that it has a unique mechanism of activity. In comparison with standard drugs, oTR showed exceptional cytotoxic activity against NCI 60 cell lines with a mutated p53 tumour suppressor gene. oTR also exhibited significant anticancer activity against several tumour models in in vivo hollow fibre assays.