Trithiocarbonates as a Novel Class of HDAC Inhibitors: SAR Studies, Isoenzyme Selectivity, and Pharmacological Profiles

Abstract

Inhibitors of histone deacetylases (HDAC) are currently developed for the treatment of cancer. These include compounds with a sulfur containing head group like depsipeptide, alkylthiols, thiocarboxylates, and trithiocarbonates with a carbonyl group in the alpha-position. In the present investigation, we report on the synthesis and comprehensive SAR analysis of HDAC inhibitors bearing a tri- or dithiocarbonate motif. Such trithiocarbonates are readily accessible from either preformed or in situ prepared alpha-halogenated methylaryl ketones. A HDAC isotype selectivity and a substrate competitive mode-of-action is shown for defined analogues. Exploration of the head group showed the necessity of the dithio-alpha-carbonyl motif for potent HDAC inhibition. Highly potent, substrate competitive HDAC6 selective inhibitors were identified (12ac:IC 50 = 65 nM and K i = 110 nM). Trithiocarbonate analogues with an aminoquinoline-substituted pyridinyl-thienoacetyl cap demonstrate a cytotoxicity profile and potency comparable to that of suberoylanilide hydroxamic acid (SAHA) as an approved cancer drug.

HDAC6: Physiological function and its selective inhibitors for cancer treatment

“…Compound 12ac (Figure 12) was described as a selective HDAC6 inhibitor of all compounds with trithiocarbonate, and compound 12ac with a phenylacetyl moiety as the CAP group displayed better selectivity for HDAC6 ( IC 50 of 65 nm) over HDAC1( IC 50 of 1.22 μM)in in vitro enzyme assays (55). The selective inhibition was also confi rmed with the result that tubulin hyperacetylation (10 μM) was stronger than that of histone 3 (55).…”

“…The selective inhibition was also confi rmed with the result that tubulin hyperacetylation (10 μM) was stronger than that of histone 3 (55). Compound 13 ( Figure 13) structurally characterized with a pyrrole-N-sulfonamide displayed an IC 50 of 9 nM for HDAC6 and an IC 50 of 2.1 μM for HDAC1 (55).…”

Inhibition of HDAC6‐dependent carcinogenesis: Emerging, new therapeutic options besides belinostat

“…Similarly, Dehmel et al have recently identified certain trithiocarbonate derivatives (12ac) that are highly selective for HDAC6 3 while Itoh et al have identified certain thiolate derivatives (16b) that demonstrate similar selectivity for HDAC6. 4 Besides these selective HDAC6 inhibitors a number of broad spectrum HDAC inhibitors have been identified that inhibit other HDAC class I and II enzymes also.…”

N-{4-[(2E)-3-(2H-1,3-Benzodioxol-5-yl)prop-2-enoyl]phenyl}quinoline-3-carboxamide

“…Previously, Dehmel et al [10] used the intermediary 2 for the construction of trithiocarbonates as HDAC (Histone deacetylase) Inhibitors.…”