Toward a Flexible Synthesis of Novel Forskolin Analogs
Paweł Marcin Szczepanik,1,2 Andrey Mikhaylov,1,2 Jakub Švenda*,1,2
1Department of Chemistry, Masaryk University, Kamenice 5, 625 00 Brno
2International Clinical Research Center, St. Anne’s University Hospital,
Pekařská 53, 656 91 Brno
e-mail: szczepanik89@gmail.com, svenda@chemi.muni.cz
Forskolin is a naturally occurring diterpene commonly used as a tool in the
biomedical research and also as a precursor to the clinically approved drug colforsin.
Forskolin was shown to work by stimulating various isoforms of the enzyme adenylyl
cyclase, which catalyze the conversion of ATP (adenosine triphosphate) to cAMP
(cyclic adenosine monophosphate).1 The identification of forskolin analogs with
improved selectivity toward a subset of these isoforms has been one of the non-trivial
challenges in the research on adenylyl cyclases.
The aim of our work is to develop a flexible synthetic route that would enable
the preparation of a series of novel forskolin analogs not accessible by semisynthesis
or through the published fully synthetic approaches.2-7
Following a plan based on
a convergence of the A-ring and C-ring fragments (‘coupling’) paired with a late-stage
functionalization (‘diversification’), we have been able to alter the structure of this
natural product at multiple positions. The isoform selectivity profile of all newly
synthesized forskolin analogs is being examined against a complete panel of
membrane-bound adenylyl cyclases.
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Pharmacol. Rev. 2017, 69, 93–139.
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6 Hylse, O.; Maier, L.; Kučera, R.; Perečko, T.; Svobodová, A.; Kubala, L.; Paruch, K.;
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7 Thomas, W. P.; Schatz, D. J.; George, D. T.; Pronin, S.V. J. Am. Chem. Soc. 2019,
141, 12246–12250.