Fully synthetic route to forskolin and development of
strategies for analog preparation
Ondřej Hylse and Jakub Švenda
Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech
Republic.
Forskolin (1) is a highly oxidized and structurally complex labdane diterpene
with important biological effects. Best described is the ability of forskolin to activate
membranous adenylyl cyclases (ACs) – enzymes that catalyze conversion of ATP to
cAMP.1 As many clinically used drugs act by indirect stimulation of ACs, there has
been a great interest in forskolin for biomedical applications. Adenylyl cyclases are
known to exist in nine isoforms and forskolin activates most of them (AC1–AC8). As
there are not many isoform-selective activators or inhibitors of ACs, we were
wondering if modification of the forskolin skeleton could provide isoform-selective
modulators of ACs.2
Majority of known forskolin analogs was made semisynthetically.3 To enable
structural modifications at unprecedented sites of forskolin, other approaches are
necessary. Densely grouped array of quaternary carbons and stereocenters present a
considerable synthetic challenge. We have recently completed the shortest fully
synthetic route to forskolin, which is scalable and allowed us to prepare hundred
miligram quantities of this natural product.
Initial studies into analog preparation will be discussed as well as preliminary
studies on the completely new and promising convergent synthesis of forskolin
analogs.
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2012, 67, 513.
[2] (a) S. Pierre, T. Eschenhagen, G. Geisslinger, K. Scholich, Nat. Rev. Drug Discov. 2009, 8, 321–335. (b) B. Pavan, C.
Biondi, A. Dalpiaz, Drug. Disc. Today 2009, 14, 982991.
[3] (a) K. B. Seamon, J. W. Daly, H. Metzger, N. J. de Souza, J. Reden, J. Med. Chem. 1983, 26, 436–439. (b) C. Pinto, D.
Papa, M. Hübner, T.-C. Mou, G. H. Lushington, R. Seifert, J. Pharmacol. Exp. Ther. 2008, 325, 2736.