title: Santacruzamate A, a potent and selective histone deacetylase inhibitor from the Panamanian marine cyanobacterium cf. Symploca sp.
abstract: A dark brown tuft-forming cyanobacterium, morphologically resembling the genus Symploca, was collected during an expedition to the Coiba National Park, a UNESCO World Heritage Site on the Pacific coast of Panama. Phylogenetic analysis of its 16S rRNA gene sequence indicated that it is 4.5% divergent from the type strain for Symploca and thus is likely a new genus. Fractionation of the crude extract led to the isolation of a new cytotoxin, designated santacruzamate A (1), which has several structural features in common with suberoylanilide hydroxamic acid [(2), SAHA, trade name Vorinostat], a clinically approved histone deacetylase (HDAC) inhibitor used to treat refractory cutaneous T-cell lymphoma. Recognition of the structural similarly of 1 and SAHA led to the characterization of santacruzamate A as a picomolar level selective inhibitor of HDAC2, a Class I HDAC, with relatively little inhibition of HDAC4 or HDAC6, both Class II HDACs. As a result, chemical syntheses of santacruzamate A as well as a structurally intriguing hybrid molecule, which blends aspects of both agents (1 and 2), were achieved and evaluated for their HDAC activity and specificity.
authors.affiliation: Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Connecticut , Storrs, Connecticut 06269, United States.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Pavlik
authors.forename: Christina Y B
authors.initials: CY
authors.lastname: Wong
authors.forename: Sophia
authors.initials: S
authors.lastname: Ononye
authors.forename: Dioxelis D
authors.initials: DD
authors.lastname: Lopez
authors.forename: Niclas
authors.initials: N
authors.lastname: Engene
authors.forename: Kerry L
authors.initials: KL
authors.lastname: McPhail
authors.forename: William H
authors.initials: WH
authors.lastname: Gerwick
authors.forename: Marcy J
authors.initials: MJ
authors.lastname: Balunas
mesh_terms: D002219:Carbamates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000458:Cyanobacteria / Q000737:chemistry* / Q000235:genetics; D003603:Cytotoxins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007893:Leishmania donovani / Q000187:drug effects; D016399:Lymphoma, T-Cell; D015394:Molecular Structure; D010176:Panama; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D002219:Carbamates; D003603:Cytotoxins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012336:RNA, Ribosomal, 16S; C586127:santacruzamate A; D000077337:Vorinostat