| Reference | [1]. Chem Biol Interact. 2016 Dec 25;260:196-207. doi: 10.1016/j.cbi.2016.10.008. Epub 2016 Oct 5.<br />
6-(3,4-Dihydro-1H-isoquinoline-2-yl)-N-(6-methoxypyridine-2-yl) nicotinamide-26 (DIMN-26) decreases cell proliferation by induction of apoptosis and downregulation of androgen receptor signaling in human prostate cancer cells.<br />
Choi HE(1), Shin JS(2), Leem DG(1), Kim SD(3), Cho WJ(4), Lee KT(5).<br />
Author information: (1)Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea. (2)Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea. (3)Department of Urology, College of Medicine, Dong-A University, Pusan, 602-715, Republic of Korea. (4)College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Yongbong-dong, Gwangju, Republic of Korea. (5)Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea. Electronic address: [email protected].<br />
Previously, we reported that 6-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(6-methylpyridin-2-yl) nicotinamide (DIMN) analogues inhibited the growth of prostate cancer cells as an anti-androgenic compound. In the present study, we evaluated cytotoxic effects of these DIMN derivatives and found that DIMN-26 most potently inhibited the proliferation of the LNCap-LN3 androgen-dependent and DU145 androgen-independent prostate cancer cells through induction of G2/M phase cell cycle arrest and subsequent apoptosis. The G2/M phase arrest was found due to increases in the activation of cdc2 (also known as cyclin-dependent kinase 1, CDK1)/cyclin B1 complex. DIMN-26 also induced apoptosis in LNCap-LN3 and DU145 prostate cancer cells through activation of caspase-3, -8, and -9, and cleavage of poly(ADP-ribose) polymerase-1 (PARP-1). In addition, DIMN-26 caused the dephosphorylation and mitochondrial accumulation of Bad protein and induced the loss of mitochondria membrane potential, consequently releasing cytochrome c into the cytosol of the cell. Furthermore, overexpression of AKT protein significantly reduced DIMN-26-induced PARP-1 cleavage and p-Bad decrease and cdc2 activation. In addition, DIMN-26 inhibited the 5α-dihydrotestosterone (DHT)-induced cell growth and proliferation and nuclear translocation and transcriptional activities of androgen receptor (AR) in LNCap-LN3 prostate cancer cells. Consistent with these findings, DIMN-26 significantly inhibited the DHT-induced expression of AR-response genes (ARGs), such as prostate-specific antigen (PSA), AR, β2-microglobulin (B2M), selenoprotein P (SEPP1), and ste20-related proline-alanine-rich kinase (SPAK) in LNCap-LN3 prostate cancer cells. Taken together, these results suggest that DIMN-26 plays a therapeutic role not only in induction of G2/M arrest and apoptosis but also in suppression of androgen receptor signaling in androgen-dependent and androgen-independent prostate cancer cells.<br />
Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.<br />
DOI: 10.1016/j.cbi.2016.10.008 PMID: 27720946<br />
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[2]. Expert Opin Drug Discov. 2021 Apr 28:1-30. doi: 10.1080/17460441.2021.1916464. Online ahead of print.<br />
1,2,3,4-Tetrahydroisoquinoline (THIQ) as privileged scaffold for anticancer de novo drug design.<br />
Faheem(1), Karan Kumar B(1), Venkata Gowri Chandra Sekhar K(2), Chander S(3), Kunjiappan S(4), Murugesan S(1).<br />
Author information: (1)Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani, India. (2)Department of Chemistry, Birla Institute of Technology and Science-Pilani, Hyderabad, India. (3)Amity Institute of Phytomedicine and Phytochemistry, Amity University Uttar Pradesh, Noida, India. (4)Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil, India.<br />
Introduction: Cancer is a dreadful disorder that is emerging as one of the leading causes of mortality across the globe. The complex tumor environment, supplemented with drawbacks of the existing drugs, has made it a global health concern. The Tetrahydroisoquinoline (THIQ) ring holds an important position in medicinal chemistry due to its wide range of pharmacological properties. Several THIQ based natural products have been previously explored for their antitumor properties, making it a vital scaffold for anticancer drug design.Areas covered: This review article addresses the potential of THIQ as anticancer agents. Various medicinal chemistry strategies employed for the design and development of THIQ analogs as inhibitors or modulators of relevant anticancer targets have been discussed in detail. Moreover, the common strategies employed for the synthesis of the core scaffold are also highlighted.Expert opinion: Evidently, THIQs have tremendous potential in anticancer drug design. Some of these analogs exhibited potent activity against various cancer molecular targets. However, there are some drawbacks, such as selectivity that need addressing. The synthetic ease for constructing the core scaffold complimented with its reactivity makes it ideal for further structure-activity relationship studies. For these reasons, THIQ is a privileged scaffold for the design and development of novel anticancer agents.<br />
DOI: 10.1080/17460441.2021.1916464 PMID: 33908322
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