Synthesis and biological evaluation of nitric oxide-donating analogues of sulindac for prostate cancer treatment |
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| Affiliation: | 1. EaStCHEM School of Chemistry, Biomolecular Sciences Research Complex, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, UK;2. Tissue Injury and Repair Group, Department of Clinical and Surgical Sciences (Surgery), University of Edinburgh, Edinburgh EH16 4SB, UK;3. Prostate Research Group, Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh EH4 2XR, UK;1. Department of Microbiology and Immunology, Pomeranian Medical University, Szczecin, Poland;2. Department of Nephrology, Transplantology, and Internal Diseases, Pomeranian Medical University, Szczecin, Poland;3. Regional Blood Donation Center, Szczecin, Poland;1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;2. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;3. From the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115,;4. Department of Biochemistry, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts 02139,;5. Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts 02111, and;6. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115;1. Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, via Pietro Giuria 9, 10125 Torino, Italy;2. Università degli Studi di Firenze, Dipartimento di Chimica, Lab. Chimica Bioinorganica, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy;3. Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, I-50019 Sesto Fiorentino (Florence), Italy |
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| Abstract: | A series of analogues of the non-steroidal anti-inflammatory drug (NSAID) sulindac 1 were synthesised tethered to nitric oxide (NO) donating functional groups. Sulindac shows antiproliterative effects against immortal PC3 cell lines. It was previously demonstrated that the effect can be enhanced when tethered to NO releasing groups such as nitrate esters, furoxans and sydnonimines. To explore this approach further, a total of fifty-six sulindac–NO analogues were prepared and they were evaluated as NO-releasing cytotoxic agents against prostate cancer (PCa) cell lines. Compounds 1k and 1n exhibited significant cytotoxic with IC50 values of 6.1 ± 4.1 and 12.1 ± 3.2 μM, respectively, coupled with observed nitric oxide release. |
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| Keywords: | Nitric oxide Sulindac analogues Furoxan Sydnonimine Prostate cancer |
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