Synthesis of new analogs of forskolin


    Viacheslav Shkepu^ ^[a], Lukáš Maier^[a],[b], Jakub Švenda^[a],[b] and Kamil Paruch^[a],[b]
                                                 ^

                   ^[a] Department of Chemistry, Masaryk University, Kamenice 5

          ^[b] International Clinical Center, St. Anne’s University Hospital, Pekařská 53

                                       Brno, Czech Republic

                        e-mail: shkepu@mail.muni.cz, paruch@chemi.muni.cz.


Forskolin, a highly oxygenated labdane diterpene originally isolated from the roots of Coleus
forskohlii, can activate individual isoforms of adenylyl cyclases (ACs). ACs catalyze the
conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), which is a key
second messenger binding to and regulating numerous downstream effector proteins, thereby
modulating various physiological functions.^1 Forskolin represents a valuable tool in biomedical
research^2 and considerable effort has been invested in the search of its analogs with improved
properties.^3 The approach recently developed at Masaryk University^4 enabled synthesis of the
des-dimethylforskolin analog 1, which showed improved selectivity against the isoforms AC5 and AC7.
This observation prompted the synthesis (and profiling) of additional synthetic analogs of
forskolin with modified position 4, namely the mono-methyl analog 2 , mono-methoxymethyl analog 3
and mono-hydroxymethyl analog 4  (Scheme 1), described herein.

                                             Scheme 1


1. C. W. Dessauer Pharmacol. Rev. 2017, 69, 9-139.

2.  P. A. Insel, R. S. Ostrom Cell. Mol. Neurobiol. 2003, 23, 305-314.

3.  R. H. Alasbahi, M. F. Melzig Pharmazie 2012, 67, 5-13.

4.  O. Hylse, L. Maier, R. Kucera, T. Perecko, A. Svobodova, L. Kubala, K. Paruch, J. Švenda
Angew. Chem. Int. Ed. 2017, 56, 12586-12589.


This work was supported by the grants CZ-OPENSCREEN: National Infrastructure for Chemical Biology
(Identification code: LM2018130), Preclinical Progression of New Organic Compounds with Targeted
Biological Activity (CZ CZ.02.1.01/0.0/0.0/16_025/0007381), and by the Bader Philanthropies.