We report on the solid-phase synthesis of a combinatorial methylated (±)-epigallocatechin gallate (EGCG) library and its biological evaluation. Epigallocatechin gallate (EGCG) and its methylated derivatives, which are members of the catechin family, exhibit various anti-cancer effects. The solid-phase synthesis of methylated EGCG involves the preparation of the α-acyloxyketone by the coupling of a solid-supported aldehyde with a ketone and an acid. The subsequent release and reductive etherification reaction of the solid-supported α-acyloxyketone provide the protected EGCG in good total yields. Sixty-four methylated EGCGs were successfully prepared. The growth-inhibitory effects of the methylated EGCG library were also examined. Although methylation of EGCG generally causes reduced growth inhibition, the growth-inhibitory effect of 7-OMe EGCGs was comparable to that of EGCG. The 7-OMe EGCGs are attractive drug candidates because of their enhanced bioavailability.
Without a trace…︁ The natural product epigallocatechin gallate (see scheme, right) and a library of derivatives were synthesized on a solid phase. Reductive etherification upon the release of the α‐acyloxy ketone intermediate from the resin provided the desired epicatechin derivatives. Bn=benzyl, PS=polystyrene, TFA=trifluoroacetic acid.
Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.
Ohne jede Spur: Der Naturstoff Epigallocatechingallat (siehe Schema rechts) und eine Bibliothek von Derivaten wurden an fester Phase synthetisiert. Eine reduktive Veretherung bei der Freisetzung des intermediären α‐Acyloxyketons vom Harz lieferte die gewünschten Epicatechin‐Derivate. Bn: Benzyl, PS: Polystyrol, TFA: Trifluoressigsäure.
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