Abstract
Background: Modified nucleosides established a prime role as therapeutic drugs.
Objective: Design and synthesis of novel truncated carbocyclic nucleoside with modified nucleobases and evaluation of their anticancer properties.
Methods: Novel truncated carbocyclic nucleoside analogues were synthesized from a versatile starting material D-ribose. The synthetic route includes stereoselective Grignard reaction, Wittig olefination, ring closing metathesis, double bond hydrogenation and Mitsunobu nucleobase condensation as the key steps. Cytotoxicity was measured using MTT assay in breast cancer cell lines (MCF7 and MDA-MB-231), ovarian cancer cell lines (IGROV1 and OVCAR8).
Result & Conclusion: The synthesized compounds were characterized using spectroscopy techniques. The synthesized compounds induced cytotoxicity in breast cancer cell lines (MCF7 and MDA-MB-231), ovarian cancer cell lines (IGROV1 and OVCAR8) while minimal effect on primary cell line. Among the eight analogues, 1b and 1d showed the highest cytotoxicity effect and induced autophagy mode of cell death. These compounds induced autophagy by inactivating AKT and mTOR pathway. In addition, PARP1 was found to be stabilized upon treatment with compound 1b and 1d and is one of the known markers associated with induction of autophagy through the AMPK/mTOR pathway after DNA damage. Taken together, these results suggest that compounds 1b and 1d inhibit cancer cell proliferation through mTOR inactivation-mediated induction of autophagy.
Keywords: Truncated, carbocyclic nucleosides, anticancer, autophagy, D-ribose, cytotoxicity.
Anti-Cancer Agents in Medicinal Chemistry
Title:Synthesis and Anticancer Properties of Novel Truncated Carbocyclic Nucleoside Analogues
Volume: 18 Issue: 10
Author(s): Balija Sivakrishna, Sehbanul Islam, Amarendra Panda, Maddi Saranya, Manas K. Santra*Shantanu Pal*
Affiliation:
- Cancer Biology Laboratory, National Centre for Cell Science, Ganeshkhind Road, Pune, Maharashtra-411007,India
- Organic Chemistry Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Bhubaneswar, Orissa 751007,India
Keywords: Truncated, carbocyclic nucleosides, anticancer, autophagy, D-ribose, cytotoxicity.
Abstract: Background: Modified nucleosides established a prime role as therapeutic drugs.
Objective: Design and synthesis of novel truncated carbocyclic nucleoside with modified nucleobases and evaluation of their anticancer properties.
Methods: Novel truncated carbocyclic nucleoside analogues were synthesized from a versatile starting material D-ribose. The synthetic route includes stereoselective Grignard reaction, Wittig olefination, ring closing metathesis, double bond hydrogenation and Mitsunobu nucleobase condensation as the key steps. Cytotoxicity was measured using MTT assay in breast cancer cell lines (MCF7 and MDA-MB-231), ovarian cancer cell lines (IGROV1 and OVCAR8).
Result & Conclusion: The synthesized compounds were characterized using spectroscopy techniques. The synthesized compounds induced cytotoxicity in breast cancer cell lines (MCF7 and MDA-MB-231), ovarian cancer cell lines (IGROV1 and OVCAR8) while minimal effect on primary cell line. Among the eight analogues, 1b and 1d showed the highest cytotoxicity effect and induced autophagy mode of cell death. These compounds induced autophagy by inactivating AKT and mTOR pathway. In addition, PARP1 was found to be stabilized upon treatment with compound 1b and 1d and is one of the known markers associated with induction of autophagy through the AMPK/mTOR pathway after DNA damage. Taken together, these results suggest that compounds 1b and 1d inhibit cancer cell proliferation through mTOR inactivation-mediated induction of autophagy.
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Cite this article as:
Sivakrishna Balija , Islam Sehbanul , Panda Amarendra , Saranya Maddi , Santra K. Manas *, Pal Shantanu *, Synthesis and Anticancer Properties of Novel Truncated Carbocyclic Nucleoside Analogues, Anti-Cancer Agents in Medicinal Chemistry 2018; 18 (10) . https://dx.doi.org/10.2174/1871520618666180322120533
DOI https://dx.doi.org/10.2174/1871520618666180322120533 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
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