Determination of the Antiproliferative Activity of New Theobromine Derivatives and Evaluation of Their In Vitro Hepatotoxic Effects

Author(s):

Maya Georgieva, Magdalena Kondeva-Burdina, Javor Mitkov, Virginia Tzankova, Georgi Momekov and Alexander Zlatkov   Pages 925 - 932 ( 8 )

Abstract:

A new series of N-substituted 1-benzyltheobromine-8-thioacetamides were designed and synthesized. Their anti-proliferative activity against human chronic myelocytic leukemia cell K562, human T-cell leukemia cell SKW-3 and human acute myeloid leukemia HL-60 was evaluated. For the tested compounds a concentrationdependent cytotoxic activity was observed, with 7g outlined as the most active compound within the series. The targed compounds were obtained in yields of 56 to 85% and their structures were elucidated by FTIR, ¹H NMR, ¹³C NMR and microanalyses. The compounds purity was proven by elemental analysis and spectral data. In general, the compounds showed low hepatotoxicity on sub-cellular and cellular level. On isolated rat microsomes only 7d showed toxic effect while theobromine, 1-benzyl-theobromine-thioacetic acid (BTTA) and the other new theobromine derivatives were devoid of toxicity. In isolated rat hepatocytes, when compared to theobromine and BTTA, 7f showed lower cytotoxic effects, and 7d exerted higher cytotoxicity. The results indicate 7g as a promising structure for the design of future compounds with low hepatotoxicity and good antiproliferative activity.

Keywords:

Antiproliferative activity, 1-benzyl-theobromine-thioacetic acid, cytotoxicity, theobromine derivatives, isolated rat microsomes and hepatocytes.

Affiliation:

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University - Sofia, 2 “Dunav” Str., 1000 Sofia, Bulgaria.

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