Design, synthesis and biological evaluation of quinoline-2-carbonitrile-based hydroxamic acids as dual tubulin polymerization and histone deacetylases inhibitors
Graphical abstract
Introduction
To avoid off-target effects, most of the currently approved drugs have been designed to target a single biological entity, usually a protein (the so-called “on-target”). However, this model has shown its limits, especially in treating complex diseases like malignant tumors and central nervous system diseases [1]. While drug combination therapies are used as an alternative approach to achieve efficacy, their benefits are often counteracted by adverse drug−drug interactions, unpredictable pharmacokinetics, additive toxicities, and poor patient compliance [2]. Multitarget drugs, where a single drug molecule can interact with several targets simultaneously, lead to new and more effective medications for various complex diseases [3,4]. They may offer some advantages such as better efficacy, superior treatment compliance, and lower risk of drug-drug interactions [5]. Consequently, in recent years, much attention has been given to discovering multitarget drugs to address the limited efficacy and resistance or toxicity associated with many single-target or combination-based therapies [6]. Multi-targeted drugs share most of the advantages of multi-component drugs but do not have many of their disadvantages, and they also have several distinct advantages of their own. However, they reveal some disadvantages, particularly in terms of their design, increased molecular weight, and sometimes difficult synthesis.
Disruption of microtubules function induces cell cycle arrest in the G2/M phase and the formation of abnormal mitotic spindles. Therefore, drugs that exert their effect by controlling the microtubule assembly either by hindering tubulin polymerization or by obstructing microtubule disassembly are important in anti-cancer therapy [7]. Various naturally occurring compounds such as paclitaxel, vinblastine, combretastatins, and colchicine exert their effect by modifying the tubulin dynamics. Tubulin polymerization inhibitors (TPIs), like combretastatin A-4 (CA-4), exhibit potent anti-vascular activity in malignant tumors [[8], [9], [10]]. CA-4 phosphate (CA-4P) has received orphan drug status from the US FDA to treat a range of thyroid and ovarian cancers [11]. CA-4 exists in two geometric configurations, cis- and trans-stilbene, but only the cis isomer of CA-4 possesses significant anti-cancer activity. Isomerization of cis CA-4 into the less active trans isomer is readily observed on storage and in vivo during metabolism, accompanied by a dramatic reduction in both anti-tubulin and anti-tumor activities [[12], [13], [14]]. Our group discovered isoCA-4 [[15], [16], [17]], a stable non-natural isomer of CA-4 having a 1,1-diarylethylene structure, which has the same biological properties as the natural CA-4. Structure-activity relationships (SAR) on the linker between A- and B-ring [18] showed that the double bond reduction decreased the activity [19]. In contrast, the use of the N–Me linker gave an excellent activity [[20], [21], [22]]. Also, we furthermore demonstrated that the traditional 3,4,5-trimethoxyphenyl A-ring of natural CA-4 and isoCA-4, which is subject to metabolism reaction (O-demethylation), could be replaced successfully by a 2-methylquinazoline 1 [23], 2-methylquinoline 3 [24], or quinoline-2-carbonitrile rings 2 and 4, [25]. The corresponding compounds (1–4) showed potent antiproliferative activity.
Histone deacetylases (HDACs) are a family of enzymes that play a crucial role in regulating gene expression by remodeling chromatin structure. They control many cancer-related cellular processes such as cell proliferation, cell migration, cell apoptosis, and angiogenesis. In several cancers, the aberrant expression of HDACs correlates with tumor onset and progression [26]. A clear association between HDAC activity, tumor growth, and cell survival has been well established in a broad spectrum of hematologic and solid tumors [27,28], including neuroblastoma, the most common solid tumor in children [29]. HDACs have been identified as attractive molecular targets in cancer therapy for these reasons. Five HDAC inhibitors (HDACi), namely SAHA, romidepsin, belinostat, panobinostat, and chidamide (approved in China), have been approved to treat hematological malignancies, including refractory cutaneous T cell lymphoma (CTCL) [30]. Despite their great success in treating hematological malignancies, most known HDACi failed to show clinical benefits in nearly all types of solid tumors when used as a single agent [31]. Simultaneously inhibiting HDAC and other targets involved in the pathogenesis of solid tumors may address this issue.
Although both TPIs and HDACi are limited by insufficient efficacy and tumor resistance [32,33], there is strong evidence that simultaneous inhibition of both tubulin polymerization and HDAC can synergistically inhibit tumor growth and improve therapeutic efficacy by limiting the occurrence of resistance [32,33]. A study has shown an interesting synergic effect of combining the microtubule depolymerizing agent vincristine and vorinostat (HDACi) in leukemia in vitro and in vivo [34]. In 2018, we found that compound isoCA-4HDi, based on the structure of isoCA-4 (Fig. 1), was a multi-target-directed ligand of tubulin and HDAC8i [32]. Since then, Yao et al. developed 2-methoxyestradiol derivatives as potent dual tubulin/HDAC2 inhibitors [35]. Duan et al. designed a series of cis-diphenylethene and benzophenone derivatives as tubulin/HDAC7 dual-targeting inhibitors [36]. Also, Chen et al. described tubulin/HDAC3 dual inhibitors based on 4-substituted methoxybenzoyl-aryl-thiazoles and entinostat (MS-275) [37]. In 2019, regarding antiproliferative activity and metabolic stability, we demonstrated the benefit of switching between the 3,4,5-trimethoxyphenyl A-ring of isoCA-4 and quinazoline or quinoline ring [23,25]. Herein, we report the design, synthesis, and biological evaluation of potent dual TP/HDAC inhibitors.
Section snippets
Chemistry
Chemical synthesis. We outlined the general synthesis of compounds 9a-9e, 12a-12d, 13a, 14a, 15a, and 17a in Scheme 1, Scheme 2, Scheme 3. We prepared the key intermediate 5 in three steps: first, we performed a Buchwald-Hartwig cross-coupling reaction between 4-chloroquinoline-2-carbonitrile and 4-methoxy-3-(methoxymethoxy)aniline, then, we methylated the obtained secondary amine in the presence of methyl iodide and sodium hydride, and finally, we realized the deprotection of MOM protective
Conclusion
Structure-activity relationship (SAR) studies have been done on the different heterocyclic substitutions on the quinoline or quinazoline moieties, as well as both on the linker of the cap part (CCH2 vs. NMe), or the linker between the cap and the ZBG. Among studied compounds, we identified novel dual TPI and HDACsi with improved antiproliferative activity and enzymatic activity against HDACs 6, 8, and 11. We selected compounds 12a and 12d as advanced leads compounds and evaluated their
Chemistry. General considerations
The compounds were all identified by 1H NMR, 13C NMR, IR, and HRMS. Melting points (mp) were recorded on a Büchi B-450 apparatus and were uncorrected. NMR spectra were performed on a Bruker AMX 200 (1H, 200 MHz; 13C, 50 MHz; 19F, 88 MHz), Bruker AVANCE 300 or Bruker AVANCE 400 (1H, 300 MHz or 400 MHz; 13C, 75 MHz or 100 MHz). Solvent peaks were used as reference values, with CDCl3 at 7.26 ppm for 1H NMR and 77.16 ppm for 13C NMR, with (CD3)2SO at 2.50 ppm for 1H NMR and 39.52 ppm for 13C NMR.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors gratefully acknowledge support of this project from CNRS, Université Paris-Saclay, and La Ligue Nationale Contre le Cancer.
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