Synthesis and biological evaluation of santacruzamate A analogues for anti-proliferative and immunomodulatory activity.
Santacruzamate A (SCA) is a natural product isolated from a Panamanian marine cyanobacterium, previously reported to have potent and selective histone deacetylase (HDAC) activity. To optimize the enzymatic and cellular activity, 40 SCA analogues were synthesized in a systematic exploration of the zinc-binding group (ZBG), cap terminus, and linker region. Two cap group analogues inhibited proliferation of MCF-7 breast cancer cells, with analogous increased degranulation of cytotoxic T cells (CTLs), while one cap group analogue reduced CTL degranulation, indicative of suppression of the immune response. Additional testing of these analogues resulted in reevaluation of the previously reported SCA mechanism of action. These analogues and the resulting structure-activity relationships will be of interest for future studies on cell proliferation and immune modulation.
Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Rd, Storrs, CT 06269, USA.
Samantha M
SM
Gromek
Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Rd, Storrs, CT 06269, USA.
James A
JA
deMayo
Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Rd, Storrs, CT 06269, USA.
Andrew T
AT
Maxwell
Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Rd, Storrs, CT 06269, USA.
Ashley M
AM
West
Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Rd, Storrs, CT 06269, USA.
Christopher M
CM
Pavlik
Department of Molecular and Cell Biology, University of Connecticut, 91 N. Eagleville Rd, Storrs, CT 06269, USA.
Ziyan
Z
Zhao
Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Rd, Storrs, CT 06269, USA.
Jin
J
Li
Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Rd, Storrs, CT 06269, USA.
Andrew J
AJ
Wiemer
Department of Molecular and Cell Biology, University of Connecticut, 91 N. Eagleville Rd, Storrs, CT 06269, USA.
Adam
A
Zweifach
Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Rd, Storrs, CT 06269, USA. Electronic address: marcy.balunas@uconn.edu.
Marcy J
MJ
Balunas
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology*
D000970:Antineoplastic Agents; D002219:Carbamates; C586127:santacruzamate A
Anti-proliferative activity; Enzyme assays; Immune modulation; Natural product analogues; Santacruzamate A