Antiproliferative and Differentiating Activities of a Novel Series of Histone Deacetylase Inhibitors

Abstract

Histone deacetylases are promising molecular targets for the development of antitumor agents. A novel series of histone deacetylase inhibitors of the hydroxamic acid type were synthesized for structure-activity studies. Thirteen tricyclic dibenzodiazepine, -oxazepine, and -thiazepine analogues were studied and shown to induce variable degrees of histone H3/H4 and tubulin acetylation in a cellular model of myeloid leukemia sensitive to all-trans retinoic acid (ATRA). Multiparametric correlations between acetylation of the three substrates, tumor cell growth inhibition, and ATRAdependent cytodifferentiation were performed, providing information on the chemical functionalities governing these activities. For two analogues, antitumor activity in the animal was demonstrated.KEYWORDS HDAC inhibitors, hydroxamic acid, retinoic acid, antiproliferative effect, differentiation H istone deacetylase (HDAC) proteins are classified in four groups (class I-IV) based on function and sequence similarity. A common observation in neoplastic cells is high level expression of class I and II HDACs with corresponding hypoacetylation of histones.1 Increased HDAC activity may play a critical role in the pathogenesis of leukemia.2 HDACs of significance for cancer cell biology reside not only in the nucleus but also in the cytoplasm, where they act on substrates other than histones. Within class I, HDACs 1, 2, and 8 are primarily found in the nucleus. Class II HDACs (HDAC 4, 5, 6, 7, 9, and 10) are able to shuttle in and out of the nucleus depending on different signals.3 HDAC 6 is primarily a cytoplasmic enzyme, deacetylating proteins like tubulin, Hsp90, and cortactin. 4 Transformed cells are generally more sensitive to HDAC inhibitor-induced growth inhibition and apoptosis than their normal counterparts.5 Hence, anticancer therapeutic strategies based on HDAC inhibitors have raised significant interest. Some of the most powerful natural and synthetic HDAC inhibitors 6 are derivatives of hydroxamic acid. Here, we describe the chemical synthesis and the pharmacologic characterization of a novel series of hydroxamic acid derivatives characterized by tricyclic dibenzo-diazepine, -oxazepine, and -thiazepine rings. As the catalytic domain of all HDAC isoforms is highly conserved, 7 our approach was to design novel molecules targeting the variable external part of the channel leading to the catalytic center. We studied the effects of a limited number of systematic modifications to the tricyclic core, keeping the hydroxamic group and the linker chain of our molecules constant. The tricyclic core was selected, as structural modifications affecting hydrogen bonding, electronic features, and angles between the two aromatic rings can be easily obtained by accessible chemical modifications. Test compounds (0.01, 0.1, 1.0, 10, and 50 μM) were initially screened using an enzymatic assay measuring the total HDAC activity in HeLa cell extracts, which resulted in the selection of 13 molecules. Scheme 1 illustrates the synthesis and structures o...

Tropolones As Lead-Like Natural Products: The Development of Potent and Selective Histone Deacetylase Inhibitors

“…Additionally, the tropolone scaffold offers several points of modification to access pockets near the metalbinding site that may impart isozyme selectivity, a feature believed to be associated with increased efficacy and lower toxicity. 10 Although some hydroxamate-bearing compounds show some selectivity, 11 most of the compounds in clinical trials are considered to be pan-HDAC inhibitors and exhibit some associated toxicity that may be related to the inhibition of the many functions of the HDAC isozymes. 10 Herein, we describe first-generation tropolones that function as potent inhibitors of the HDAC enzyme and display significant cytotoxicity against T-lymphocyte cancer cell lines.…”

One Pot Solvent-Free Synthesis of Benzodiazepinones Catalyzed by CuI

“…而化合物 6 是一类苯二氮䓬酮结构的组蛋 白去乙酰化酶抑制剂的重要中间体 [13] . 组蛋白去乙酰 化酶抑制剂具有干扰与组蛋白去乙酰化酶的功能, 其对 肿瘤细胞迁移、侵袭、转移具有抑制作用, 已成为肿瘤 靶向治疗的研究新热点.…”

“…我们采用本文所述合成方法, 分两步得到了这类组蛋白去乙酰化酶抑制剂的重要中 间体化合物 6, 两步总收率 59.9%(Scheme 3B). 8, 157.7, 155.4, 147.0, 140.2, 129.7, 124.7, 124.2, 124.2, 123.1, 121.46, 120.9, 120.8, 120.5, 120.3, 119.8, 117.3, 117 166.9, 151.3, 138.7, 134.1, 129.5, 126.5, 124.6, 123.4, 123.4, 121.6, 121.4, 121.2, 119.9 170.3, 150.7, 141.9, 121.0, 120.2, 118.2, 114.8, 55.7, 48.9, 41.7 173.4, 148.3, 133.6, 132.0, 120.1, 119.3, 61.25, 52.3, 31.7, 29.5, 23.6, 22.5;HRMS calcd for C 13 H 17 N 2 O 217.1335HRMS calcd for C 13 H 17 N 2 O 217. , found 217.1334 8, 152.2, 136.4, 131.0, 127.0, 118.9, 115.1, 57.1, 51.4, 30.6, 29.2, 21.8 2, 141.3, 123.2, 120.9, 119.8, 114.2, 60.2, 55.7, 50.6, 30.8, 28.7, 23.0, 21.4 167.52, 159.75, 150.59, 144.62, 140.41, 139.48, 132.86, 130.11, 129.69, 124.47, 122.98, 121.46, 121.25, 119.78, 119.07, 118.91, 117.08, 113.91, 112.05, 55.20 59.9% [13] . 173.19, 167.62, 152.06, 145.84, 133.26, 132.08, 131.91, 125.76, 124.97, 124.21, 123.54, 121.39, 120.58, 118.68, 51.14, 48.15, 33.17, 26.87, 25.34, 23.96 …”

Synthesis of new seven-membered benzo-fused heterocyclic ortho-dicarbonitriles

“…For instance, tricyclic dibenz-[b,f]oxepine is an important structural fragment present in natural compounds [2,3] capable of inhibiting the cancer cells growth [4], exhibiting the antiphlogistic [5], neuroleptic [6], and other types of action [7,8]. Another no less important specimen of these heterocyclic class, dibenz[b,f] [1,4]oxazepine, also is one of key components of psychoactive drugs [9], antagonists of prostaglandin receptors [10], progesterone [11], inhibitors of kinase [12] and histone deacetylase [13].…”