Efficient Synthesis and Bioevaluation of Novel Dual Tubulin/Histone Deacetylase 3 Inhibitors as Potential Anticancer Agents

Abstract

Novel dual HDAC3/tubulin inhibitors were designed and efficiently synthesized by combining the pharmacophores of SMART (tubulin inhibitor) and MS-275 (HDAC inhibitor), among which compound 15c was found to be the most potent and balanced HDAC3/tubulin dual inhibitor with high HDAC3 activity (IC 50 = 30 nM) and selectivity (SI > 1000) as well as excellent antiproliferative potency against various cancer cell lines, including an HDAC-resistant gastric cancer cell line (YCC3/7) with IC 50 values in the range of 30−144 nM. Compound 15c inhibited B16-F10 cancer cell migration and colony formation. In addition, 15c demonstrated significant in vivo antitumor efficacy in a B16-F10 melanoma tumor model with a better TGI (70.00%, 10 mg/kg) than that of the combination of MS-275 and SMART. Finally, 15c presented a safe cardiotoxicity profile and did not cause nephro-/ hepatotoxicity. Collectively, this work shows that compound 15c represents a novel tubulin/HDAC3 dual-targeting agent deserving further investigation as a potential anticancer agent.

Discovery of Novel Histone Deacetylase 6 (HDAC6) Inhibitors with Enhanced Antitumor Immunity of Anti-PD-L1 Immunotherapy in Melanoma

“…We previously reported that there are two approaches to overcome the drawbacks (e.g., toxicity and drug resistance) associated with pan-HDAC inhibitors: one is to develop HDAC-based dual-acting agents, and the other is to design isoform-selective HDACis . Recently, we discovered a series of novel dual HDAC/tubulin inhibitors . Among them, compound 12c exhibited potent HDAC6-inhibitory activity with an IC 50 of 1.15 μM (Figure ), and was 38-fold and 8-fold more selective for HDAC6 over HDAC7 and HDAC3, respectively.…”

“…28 Recently, we discovered a series of novel dual HDAC/tubulin inhibitors. 29 Among them, compound 12c exhibited potent HDAC6-inhibitory activity with an IC 50 of 1.15 μM (Figure 2), and was 38-fold and 8-fold more selective for HDAC6 over HDAC7 and HDAC3, respectively. It also displayed high antiproliferative activity against a panel of cancer cell lines including an HDAC-resistant gastric cancer cell line with IC 50 values in the nanomolar range (e.g., IC 50 = 100 nM for HCT-116 cells).…”

Sustainable Production of Bioactive Molecules from C‐Lignin‐Derived Propenylcatechol

“…The slow conversion of 6 to 7 is possibly attributed to the Kornblum oxidation mediated by DMSO. [48] The analogs of 6 and 7 have been proven to be important intermediates of some known bioactive compounds, such as nordihydroguaiaretic acid (antioxidant and anticancer), [49] SMART analogs (tubulin inhibitor), [50] corbasil, [51] imidazopyridines, [52] quinoxalines. [53] (Schemes S1-S4).…”

Discovery of Novel Src Homology-2 Domain-Containing Phosphatase 2 and Histone Deacetylase Dual Inhibitors with Potent Antitumor Efficacy and Enhanced Antitumor Immunity

“…Histone deacetylases (HDACs) are important epigenetic regulators and play a key role in chromosome structural modification. HDACs stimulate gene expression by regulating the acetylation levels of various substrates, including histone and nonhistone proteins. − Heretofore, 18 HDACs have been identified in humans, which are classed into five subfamilies: class I (HDAC1, 2, 3, 8), class IIa (HDAC 4, 5, 7, 9), class IIb (HDAC 6, 10), class III (Sirtuins), and class IV (HDAC11). Among them, the zinc-dependent class I HDACs are overexpressed in many types of cancer and have become attractive targets for anticancer therapy. , To date, five HDAC inhibitors have been approved for the clinical treatment of hematological malignancies (Figure ).…”