title: Synthesis of Novel Hybrids Inspired from Bromopyrrole Alkaloids Inhibiting MMP-2 and -12 as Antineoplastic Agents.
abstract: Synthesis of novel set of forty semicarbazide/thiosemicarbazide hybrids inspired from marine bromopyrrole alkaloids is reported. Biological screening of these hybrids against a panel of five human cancer cell lines identified a number of hits endowed with interesting cytotoxicity profile. Compounds 5c and 5e (IC50  = 0.03 μm), 5t (IC50  = 0.03 μm), 4s (IC50  = 0.07 μm), and 5n (IC50  = 0.01 μm) displayed maximum cytotoxicity toward hormone-dependent breast cancer cells MCF7, hepatic cancer cells WRL68, colon cancer cells CaCO2 and mouth and oral cancer cells KB403, respectively. The most active hits were further investigated for their potential to inhibit MMP-2 and MMP-12. Compound 5e showed maximum activity (IC50  = 1.8 μm) toward MMP-2. Further, we preformed anti-invasive assay on the most active compounds, where CaCO2 tumor cell migration was significantly decreased (77.9%) by hybrid 5e. The non-toxicity toward human VERO cells (IC50  = 83.1 to 231.8 μm) indicated the selectivity of most active hits (5c, 5e, 5t and 5n) toward cancer cells.
authors.affiliation: Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa.
authors.forename: Rajesh A
authors.initials: RA
authors.lastname: Rane
authors.affiliation: Piramal Life Science Ltd, Goregaon, Mumbai, India.
authors.forename: Shital S
authors.initials: SS
authors.lastname: Naphade
authors.affiliation: S. P. P. School of Pharmacy and Technology Management, NMIMS University, Vile Parle, Mumbai, India.
authors.forename: Pavan Kumar
authors.initials: PK
authors.lastname: Bangalore
authors.affiliation: Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa.
authors.forename: Mahesh B
authors.initials: MB
authors.lastname: Palkar
authors.affiliation: Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa.
authors.forename: Harun M
authors.initials: HM
authors.lastname: Patel
authors.affiliation: Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa.
authors.forename: Mahamadhanif S
authors.initials: MS
authors.lastname: Shaikh
authors.affiliation: Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa.
authors.forename: Wesam S
authors.initials: WS
authors.lastname: Alwan
authors.affiliation: Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa.
authors.forename: Rajshekhar
authors.initials: R
authors.lastname: Karpoormath
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012663:Semicarbazides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; D011758:Pyrroles; D012663:Semicarbazides; C005151:thiosemicarbazide; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12
keywords: MMP inhibitors; antineoplastic agents; bromopyrrole alkaloids; natural product; semicarbazides; thiosemicarbazides