TY - JOUR
T1 - Synthesis and Antineoplastic Evaluation of Mitochondrial Complex II (Succinate Dehydrogenase) Inhibitors Derived from Atpenin A5
AU - Wang, Hezhen
AU - Huwaimel, Bader
AU - Verma, Kshitij
AU - Miller, James
AU - Germain, Todd M.
AU - Kinarivala, Nihar
AU - Pappas, Dimitri
AU - Brookes, Paul S.
AU - Trippier, Paul C.
N1 - Funding Information:
This work was funded by Texas Tech University Health Sciences Center School of Pharmacy. B.H. thanks the Kingdom of Saudi Arabia Cultural Mission to the USA for a graduate studentship. Work in the research group of P.S.B. is funded by a grant from the US National Institutes of Health (R01-HL071158).
Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2017/7/6
Y1 - 2017/7/6
N2 - Mitochondrial complex II (CII) is an emerging target for numerous human diseases. Sixteen analogues of the CII inhibitor natural product atpenin A5 were prepared to evaluate the structure–activity relationship of the C5 pyridine side chain. The side chain ketone moiety was determined to be pharmacophoric, engendering a bioactive conformation. One analogue, 1-(2,4-dihydroxy-5,6-dimethoxypyridin-3-yl)hexan-1-one (16 c), was found to have a CII IC50 value of 64 nm, to retain selectivity for CII over mitochondrial complex I (>156-fold), and to possess a ligand-lipophilicity efficiency (LLE) of 5.62, desirable metrics for a lead compound. This derivative and other highly potent CII inhibitors show potent and selective anti-proliferative activity in multiple human prostate cancer cell lines under both normoxia and hypoxia, acting to inhibit mitochondrial electron transport.
AB - Mitochondrial complex II (CII) is an emerging target for numerous human diseases. Sixteen analogues of the CII inhibitor natural product atpenin A5 were prepared to evaluate the structure–activity relationship of the C5 pyridine side chain. The side chain ketone moiety was determined to be pharmacophoric, engendering a bioactive conformation. One analogue, 1-(2,4-dihydroxy-5,6-dimethoxypyridin-3-yl)hexan-1-one (16 c), was found to have a CII IC50 value of 64 nm, to retain selectivity for CII over mitochondrial complex I (>156-fold), and to possess a ligand-lipophilicity efficiency (LLE) of 5.62, desirable metrics for a lead compound. This derivative and other highly potent CII inhibitors show potent and selective anti-proliferative activity in multiple human prostate cancer cell lines under both normoxia and hypoxia, acting to inhibit mitochondrial electron transport.
KW - anticancer agents
KW - atpenin A5
KW - mitochondria
KW - mitochondrial complex II
KW - succinate dehydrogenase
UR - http://www.scopus.com/inward/record.url?scp=85021171930&partnerID=8YFLogxK
U2 - 10.1002/cmdc.201700196
DO - 10.1002/cmdc.201700196
M3 - Article
C2 - 28523727
AN - SCOPUS:85021171930
VL - 12
SP - 1033
EP - 1044
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
IS - 13
ER -