title: Design and synthesis of pyrrolobenzodiazepine-gallic hybrid agents as p53-dependent and -independent apoptogenic signaling in melanoma cells.
abstract: A new class of pyrrolo[2,1-c][1,4]benzodiazepine-Gallic hybrid agents (PBD-GA) conjugated through alkyl spacers has been designed and synthesized. The combination of these two core pharmacophores with modification in the C-8 position of the PBD ring with alkyl spacers afforded oxygen-tethered compounds 5a-5d and amide-tethered analogues 11a-11d with improved anticancer activity for two melanoma cell lines, A375 and RPMI7951, differing in their p53 status. The agents 5a-5d were cytotoxic in melanoma compared to agents 11a-11d. In particular, compounds 5b and 5c were found to possess the most potent activity compared with other hybrid agents and were proved with the help of quantitative structure activity relationship studies (QSAR). These PBD conjugates caused S phase arrest for the A375 cell line via increased reactive oxygen species (ROS) generation, deoxyribonucleic acid (DNA) damage, ataxia telangiectasia mutated (ATM)/ATM-Rad3-related (ATR) and checkpoint kinases 1 (Chk1) activation. Moreover, the PBD-GA induced A375 apoptotic cell death followed through p53 (ATM downstream target) increase, B-cell leukemia-xL (Bcl-xL) and mitochondrial membrane potential (ΔΨmt) decrease, cytochrome c release, and caspase-3/Poly Adp Ribose Polymerase (PARP) cleavage. On the other hand, mutant p53 RPMI7951 cell death occurred by PBD-GA-mediated mitochondria- and caspase-dependent pathways via lysosomal membrane permeabilization (LMP), but not through p53 signaling. Finally, compound 5b was shown to reduce murine melanoma size in a mouse model. These results suggest that the PBD-GA could be used as a useful chemotherapeutic agent in melanoma with activated p53 or mutant p53.
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Chou
authors.affiliation: Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Gopal Chandru
authors.initials: GC
authors.lastname: Senadi
authors.affiliation: School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chung-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Surgery, School of Medicine, Kaohsiung Medical University, Taiwan.
authors.forename: Kung-Kai
authors.initials: KK
authors.lastname: Kuo
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ying-Ting
authors.initials: YT
authors.lastname: Lin
authors.affiliation: Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jeh-Jeng
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jia-Hau
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: wphu@kmu.edu.tw.
authors.forename: Wan-Ping
authors.initials: WP
authors.lastname: Hu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001569:Benzodiazepines / Q000737:chemistry* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D005707:Gallic Acid / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D011758:Pyrroles / Q000737:chemistry* / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D011758:Pyrroles; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines; D005707:Gallic Acid
keywords: Antitumor; Free radical; Gallic acid; Melanoma; Mitochondria; Pyrrolobenzodiazepine