Sivakrishna Balija, Islam Sehbanul, Panda Amarendra, Saranya Maddi, Santra Manas K, Pal Shantanu
Organic Chemistry Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Bhubaneswar, Orissa 751007, India.
Cancer Biology Laboratory, National Centre for Cell Science, Ganeshkhind Road, Pune, Maharashtra-411007, India.
Anticancer Agents Med Chem. 2018;18(10):1425-1431. doi: 10.2174/1871520618666180322120533.
Modified nucleosides established a prime role as therapeutic drugs.
Design and synthesis of novel truncated carbocyclic nucleoside with modified nucleobases and evaluation of their anticancer properties.
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.
修饰核苷作为治疗药物发挥着重要作用。
设计并合成具有修饰碱基的新型截短碳环核苷，并评估其抗癌特性。
以通用起始原料D-核糖合成新型截短碳环核苷类似物。合成路线包括立体选择性格氏反应、维蒂希烯烃化反应、关环复分解反应、双键氢化反应和光延碱基缩合反应等关键步骤。使用MTT法在乳腺癌细胞系（MCF7和MDA-MB-231）、卵巢癌细胞系（IGROV1和OVCAR8）中测定细胞毒性。
采用光谱技术对合成的化合物进行表征。合成的化合物在乳腺癌细胞系（MCF7和MDA-MB-231）、卵巢癌细胞系（IGROV1和OVCAR8）中诱导细胞毒性，而对原代细胞系影响极小。在八种类似物中，1b和1d表现出最高的细胞毒性作用，并诱导细胞死亡的自噬模式。这些化合物通过使AKT和mTOR通路失活来诱导自噬。此外，发现用化合物1b和1d处理后PARP1被稳定化，并且是与DNA损伤后通过AMPK/mTOR通路诱导自噬相关的已知标志物之一。综上所述，这些结果表明化合物1b和1d通过mTOR失活介导的自噬诱导来抑制癌细胞增殖。
