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Synthesis and identification of a new class of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzo[d]thiazole derivatives as potent antileukemic agents

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Summary

Benzothiazoles are multitarget agents with broad spectrum of biological activity. Among the antitumor agents discovered in recent years, the identification of various 2-(4-aminophenyl) benzothiazoles as potent and selective antitumor drugs against different cancer cell lines has stimulated remarkable interest. Some of the benzothiazoles are known to induce cell cycle arrest, activation of caspases and interaction with DNA molecule. Based on these interesting properties of benzothiazoles and to obtain new biologically active agents, a series of novel 4,5,6,7-tetrahydrobenzo[d]thiazole derivatives 5(a–i) were synthesized and evaluated for their efficacy as antileukemic agents in human leukemia cells (K562 and Reh). The chemical structures of the synthesized compounds were confirmed by 1H NMR, LCMS and IR analysis. The cytotoxicity of these compounds were determined using trypan blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Results showed that, these compounds mediate a significant cytotoxic response to cancer cell lines tested. We found that the compounds having electron withdrawing groups at different positions of the phenyl ring of the thiourea moiety displayed significant cytotoxic effect with IC50 value less than 60 μM. To rationalize the role of electron withdrawing group in the induction of cytotoxicity, we have chosen molecule 5g (IC50 ~15 μM) which is having chloro substitution at ortho and para positions. Flow cytometric analysis of annexin V-FITC/ propidium iodide (PI) double staining and DNA fragmentation suggest that 5g can induce apoptosis.

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Acknowledgements

We are grateful to University Grants Commission (UGC), Government of India for financial support to KSR under the projects vide no. F. 31-143/2005(SR), UGC-SAP (Phase I) vide No. F. 540/10/2004–05 (SAP I) Programme. SCR acknowledges support from Lady Tata Memorial Trust international award for leukemia research (London). DSP and KV are grateful to Council of Scientific and Industrial Research, New Delhi for financial support under CSIR-SRF order No. 09/119(0173)2K8 EMR-I and order No. 09/119(0172)2K8 EMR-I, respectively.

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Authors and Affiliations

  1. Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570 006, India

    D. S. Prasanna, B. Raghava, K. Vinaya, S. R. Ranganatha & K. S. Rangappa

  2. Department of Biochemistry, Indian Institute of Science, Bangalore, 560 012, India

    C. V. Kavitha & Sathees C. Raghavan

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  1. D. S. Prasanna
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  2. C. V. Kavitha
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  3. B. Raghava
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  4. K. Vinaya
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  6. Sathees C. Raghavan
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  7. K. S. Rangappa
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Correspondence to K. S. Rangappa.

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Prasanna, D.S., Kavitha, C.V., Raghava, B. et al. Synthesis and identification of a new class of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzo[d]thiazole derivatives as potent antileukemic agents. Invest New Drugs 28, 454–465 (2010). https://doi.org/10.1007/s10637-009-9276-y

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