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.
