title: Design and Synthesis of Antitumor Heck-Coupled Sclareol Analogues: Modulation of BH3 Family Members by SS-12 in Autophagy and Apoptotic Cell Death.
abstract: Sclareol, a promising anticancer labdane diterpene, was isolated from Salvia sclarea. Keeping the basic stereochemistry-rich framework of the molecule intact, a method for the synthesis of novel sclareol analogues was designed using palladium(II)-catalyzed oxidative Heck coupling reaction in order to study their structure-activity relationship. Both sclareol and its derivatives showed an interesting cytotoxicity profile, with 15-(4-fluorophenyl)sclareol (SS-12) as the most potent analogue, having IC50 = 0.082 μM against PC-3 cells. It was found that SS-12 commonly interacts with Bcl-2 and Beclin 1 BH3 domain proteins and enhances autophagic flux by modulating autophagy-related proteins. Moreover, inhibition of autophagy by autophagy inhibitors protected against SS-12-induced apoptosis. Finally, SS-12 effectively suppressed tumor growth in vivo in Ehrlich's ascitic and solid Sarcoma-180 mouse models.
authors.lastname: Shakeel-u-Rehman
authors.forename: Bilal
authors.initials: B
authors.lastname: Rah
authors.forename: Shabir H
authors.initials: SH
authors.lastname: Lone
authors.forename: Reyaz Ur
authors.initials: RU
authors.lastname: Rasool
authors.forename: Saleem
authors.initials: S
authors.lastname: Farooq
authors.forename: Debasis
authors.initials: D
authors.lastname: Nayak
authors.affiliation: ⊥School of Bioscience and Technology, Division of Medical Biotechnology, VIT University, Vellore, Tamilnadu-632014, India.
authors.forename: Naveed Anjum
authors.initials: NA
authors.lastname: Chikan
authors.forename: Souneek
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Akanksha
authors.initials: A
authors.lastname: Behl
authors.forename: Dilip Manikaro
authors.initials: DM
authors.lastname: Mondhe
authors.forename: Anindya
authors.initials: A
authors.lastname: Goswami
authors.forename: Khursheed Ahmad
authors.initials: KA
authors.lastname: Bhat
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D015195:Drug Design; D005260:Female; D054879:Halogenation; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D027544:Salvia / Q000737:chemistry; D012510:Sarcoma 180 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D004224:Diterpenes; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C070760:sclareol; D058570:TOR Serine-Threonine Kinases