Thymidylate synthase activity and the cell growth are inhibited by the ?-carboline-benzoquinolizidine alkaloid deoxytubulosine

Rao, K. N.; Bhattacharya, R.K.; Venkatachalam, S. R.

doi:10.1002/(sici)1099-0461(1998)12:3<167::aid-jbt5>3.0.co;2-j

Cited by 6 publications

References 21 publications

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Antitumor and neurotoxic effects of novel harmine derivatives and structure‐activity relationship analysis

Chen

Chao

Chen

et al. 2005

Intl Journal of Cancer

141

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Beta-carboline alkaloids such as harmine are present in medicinal plants such as Peganum harmala that have been used as folk medicine in anticancer therapy. In our study, 9 harmine derivatives (including harmine) were investigated for their antitumor effects and acute toxicities in mice, and the structure-activity relationship (SAR) was also analyzed. Administration of these compounds resulted in tumor inhibition rates of 15.3-49.5% in mice bearing Lewis Lung Cancer, sarcoma180 or HepA tumor, with the highest value of 49.5% from compound 6. Acute toxicity studies showed that all these compounds except compounds 2 and 5 caused remarkable acute neurotoxicities manifested by tremble, twitch and jumping. SAR analysis indicated that the formate substitution at R3 of the tricyclic skeleton reduced their neurotoxicity, while the short alkyl or aryl substitution at R9 increased the antitumor activity. The harmine and its derivatives resulted in in vitro cytotoxicity ( Key words: harmine, ␤-carboline alkaloid, antitumor effect, apoptosis, structure-activity relationship There is an increasing interest in the discovery of novel antitumor agents from natural resources. Over 46% (98/211) of newly approved drugs and new drug candidates (excluding biologics) for cancer therapy by Food and Drug Administration were of natural origin during the period from 1989 to 1995. 1 The ␤-carboline alkaloids present in medicinal plants such as Peganum harmala and Eurycoma longifolia have recently drawn attention due to their antitumor properties. Those plants have been used for the treatment of various diseases including cancers and malaria in Oriental traditional medicine for 2 millennia. The scientific basis for the use of these compounds as anticancer agents has been initially explored. The extracts from Peganum harmala exhibited significant tumor inhibition effect in tumor-bearing mice, 2 and the major active components in the extracts were identified to be harmine, harmaline, harmalol and Harman (all ␤-carbolines). In vitro studies have shown that ␤-carbolines such as harmine were highly cytotoxic and significantly inhibited tumor cell growth with apoptotic effect. [2][3][4][5][6][7][8] Further mechanistic studies indicated that some ␤-carbolines could inhibit DNA synthesis and intercalate into the DNA helix and were inhibitors of DNA topoisomerase I and II. 9 -14 Moreover, many ␤-carbolines such as harmine were potent and specific inhibitors of cyclin-dependent kinases (CDKs) with most compounds inhibiting CDK2 and CDK 5 to the same extent. 15

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Antitumor and neurotoxic effects of novel harmine derivatives and structure‐activity relationship analysis

Chen

Chao

Chen

et al. 2005

Intl Journal of Cancer

141

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Pharmacodynamic assay of thymidylate synthase activity in peripheral blood mononuclear cells

et al. 2013

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A simple, selective, and sensitive method utilizing tritium ((3)H) release from (3)H-deoxyuridine 5'-monophosphate (dUMP) substrate for accurate and precise determination of the low basal thymidylate synthase activity (TSA) in normal healthy peripheral blood mononuclear cells (PBMCs) was developed and validated. The method is based on the removal of the remaining substrate after the TSA reaction by absorption onto activated carbon and measurement of the supernatant fluid by liquid scintillation counting. The method background was substantially decreased by using lyophilized substrate and optimized binding conditions of remaining substrate onto carbon after TSA reaction. The concentration of cofactor N (5),N (10) methylene-(6R,S)-tetrahydrofolate was increased to obtain maximal TSA. Method sensitivity was further increased by omission of ethylenediaminetetraacetic acid from the reaction mix and by using longer reaction times. The validation parameters included specificity, linearity, sensitivity, precision, and stability. The lower limit of quantification was 25 μg PBMC cytosolic lysate, which released 1.4 pmol (3)H/h. TSA was stable in PBMC pellets stored for 6 months at -80 °C. The applicability of the method was demonstrated by the successful determination of TSA in PBMC cytosolic lysates from ten healthy volunteers with and without the specific TSA inhibitor FdUMP.

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Alkaloids

Wiart

2013

Lead Compounds From Medicinal Plants for the Treatment of Cancer

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Thymidylate synthase activity and the cell growth are inhibited by the ?-carboline-benzoquinolizidine alkaloid deoxytubulosine

Cited by 6 publications

References 21 publications

Antitumor and neurotoxic effects of novel harmine derivatives and structure‐activity relationship analysis

Antitumor and neurotoxic effects of novel harmine derivatives and structure‐activity relationship analysis

Pharmacodynamic assay of thymidylate synthase activity in peripheral blood mononuclear cells

Alkaloids

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