Re-exploration of tetrahydro-β-carboline scaffold: Discovery of selective histone deacetylase 6 inhibitors with neurite outgrowth-promoting and neuroprotective activities

Design, synthesis and antiproliferative evaluation of tetrahydro-β-carboline histone deacetylase inhibitors bearing an aliphatic chain linker

“…The chemical information for compounds 7b-f can be found in ref. 26. a Assays were performed by National Cancer Institute (NCI) at a single concentration (10 mM).…”

“…The chemical information for compound 8b can be found in ref. 26 5.1.3 General procedure C: preparation of target compounds 9a-i and 13a-j. (i) To a mixed solution of methanol and water (V : V = 5 : 1) were added various esters (1 equiv.)…”

“…Hence, structural optimization on the THbC scaffold is a promising strategy for drug discovery. 25,26 In this paper, we attached a typical aliphatic linker and the ZBG hydroxamic acid present in multiple HDACis to this scaffold, and the chirality of the two chiral centers (C1 and C3) of the THbC derivatives were also adjusted through the introduction of various substituents (Fig. 2).…”

“…As outlined in Schemes 1 and 2, the key procedure for the synthesis of THbC derivatives was the application of the Pictet-Spengler cyclization from chiral tryptophan and aldehyde precursors according to our previous reports. 26,27 Under acidic conditions, the use of L-tryptophan (6) or D-tryptophan (10) with different aldehydes gave predominantly the desired thermodynamically stable trans-THbCs 7a-g or 11a-g. Alkylation of the N2 position with allyl bromide gave intermediates 8a-b using potassium carbonate as the base (Scheme 1). The building blocks 7a-g and 8a-b were then hydrolyzed and subsequently coupled with commercially available 6-amino-N-hydroxyheptanamide or 7-amino-N-hydroxyhexanamide to provide the corresponding esters, which upon treatment with an aqueous NH 2 OH/NaOH solution yielded the targeted (1R,3S)-THbCs 9a-i.…”