Future medicinal chemistry最新文献

Aim: Human carbonic anhydrases (hCAs) are involved in many physiological processes including respiration, pH control, ion transport, bone resorption, and gastric fluid secretion. Recently, CA IX and CA XII have been studied for their role in cancer diseases, motivating the design of inhibitors of these isoforms.

Material and method: Here, we used the tail approach to design a new series of monoaryl (1a-i) and bicyclic (1j-n) benzensulfonamide derivatives CA IX and CA XII inhibitors. All synthesized compounds were investigated toward a panel of hCAs, and most of them exhibited potent CA inhibitory activity for CA II, CA IX and CA XII with K_i values. In silico studies were performed to investigate the binding mode between inhibitors and CA.

Results and conclusion: The best compound was 1i that showed a low nanomolar range of K_i value as CA inhibitor (K_i = 9.4, 5.6 and 6.3 nM hCA II, IX and XII, respectively).

Reversible protein ubiquitination is a crucial factor in cellular homeostasis, with Ubiquitin-Specific Protease 1 (USP1) serving as a key deubiquitinase involved in DNA damage response (DDR) and repair mechanisms in cancer. While ubiquitin ligases have been extensively studied, research on the reverse process of ubiquitination, particularly the mechanisms involving USP1, remains relatively limited. USP1 is overexpressed in various cancers, influencing tumor initiation and progression by regulating multiple associated proteins. Inhibiting USP1 effectively suppresses tumor proliferation and migration and may help overcome resistance to cisplatin and PARP inhibitors. As a potential synthetic lethal target, USP1 demonstrates significant research potential. This review highlights the biological mechanisms of USP1 in cancer progression, the signaling pathways it regulates, and the latest advancements in USP1 inhibitors, while also analyzing the opportunities and challenges of targeting USP1. By adopting the perspective of "the other side of the coin," this review aims to underscore the crucial yet often overlooked role of the deubiquitinase USP1, contrasting it with the extensively studied ubiquitin ligases, and emphasizing its therapeutic potential in cancer treatment.

Background: Due to the divers biological applications of Cu(II) complexes, we in this study reports the various Cu(II) complexes. The study aims to synthesize and assess new Cu(II) complexes as powerful β-glucuronidase inhibitors.

Methods: Five Schiff base ligands and their complexes were synthesized, characterized, and screened against β-glucuronidase inhibitory activity.

Results: In the series, compounds 3e, 3c, 2b, and 2c ascribed powerful inhibition ranging from (IC₅₀  = 3.0 ± 0.7 µM) to (IC₅₀  = 19.2 ± 0.8 µM). A precise and particular arrangement of atoms is suggested by the triclinic p-1 space group and the existence of a single molecule in an asymmetric unit, which are indispensable for the reactivity as well as the stability of the compounds. The analysis of the Hirshfeld surface provides information about the hydrogen intermolecular and π-π interactions. Based on molecular docking, binding potency increasing by complexation 3a-e compared to ligands 2a-e as well as reference Saccharic acid and uronic isofagomine inhibitor, suggesting that it may be a potent inhibitor of these receptors.

Conclusion: The work recognizes latent active compounds for novel β-glucoronidase inhibitors, by further support these may be harnessed for the development of potent drugs.

Aim: New phenyldiazene scaffold-linked heterocyclic pyrazole, pyrimidinone, pyrimidinthione, and/or triazine rings have been developed and synthesized.

Methods & results: Cytotoxicity of our derivatives was estimated on four cancer and VERO normal cell lines targeting EGFR^T790M (epidermal growth factor receptor) and VEGFR-2 (vascular endothelial growth factor receptor-2) enzymes. Our new derivatives selectively inhibited both VEGFR-2 and EGFR as they have the essential structural requirements for inhibitors of both receptors. Derivative 14 was the most active on A549, HCT116, HepG2, and MCF-7 cancers with half-maximal inhibitory concentration (IC₅₀) = 5.50, 9.77, 7.12, and 7.85 µM respectively. The assessed derivatives 5, 7, 8, 9, 10, 12 and 14 showed IC₅₀ = 54.40-62.60 μM against normal VERO (normal kidney) cells with low toxicity. In addition, derivatives 14, 8, 10, 7 and 9 were discovered to be very good active inhibitors of VEGFR-2 at IC₅₀ values of 1.15, 1.35, 140, 1.78 and 1.90 µM, respectively. Furthermore, derivatives 14, 10, 8, and 9 strongly repressed EGFR^T790M with IC₅₀ = 0.28, 0.33, 0.35, and 0.50 µM correspondingly. Additionally, the highly active compounds 8, 10, and 14 showed good ADMET profile.

Conclusion: Our derivatives could be considered as anticancer agents with dual VEGFR-2 and EGFR^T790M inhibition.

Aims: Drug-loaded poly(lactic-co-glycolic acid) (PLGA) scaffolds were fabricated using a mold-less technique to investigate whether the combined delivery of both Y15 (FAK inhibitor) and metformin would result in enhanced effects on cell viability compared to the release of each drug alone for the treatment of platinum-resistant ovarian cancer (PROC).

Materials & methods: Scaffolds were fabricated using an easy and economical mold-less technique that combined PLGA and the drugs (i.e. metformin and/or Y15) in tetraglycol and injected in PBS, to form a globular morphology.

Results: The exposure of cells to metformin and Y15 resulted in a significantly enhanced cytotoxic efficacy compared to single-drug treatment with either metformin or Y15. When the drugs were delivered using the PLGA scaffolds, the combination of the two drugs was significantly more cytotoxic compared to scaffolds containing metformin only and Y15 only.

Conclusions: The combination of metformin and Y15 can result in an increase in antitumor activity in PROC cells through apoptosis. The delivery of both drugs from the PLGA biomaterial scaffold allowed for a more enhanced combinational effect compared to the utilization of free drugs (without a scaffold) and should be further explored as a promising treatment of PROC.

The escalating cases of type II diabetes combined with adverse side effects of current antidiabetic drugs spurred the advancement of innovative approaches for the management of postprandial glucose levels. α-Amylase is an endoamylase responsible for the breakdown of internal α-1,4-glycosidic linkages in dietary starch, producing oligosaccharides. Subsequently, α-glucosidase degraded these oligosaccharides to monosaccharides, which are absorbed into the bloodstream and become available to the body. The inhibitors of α-amylase reduced the digestibility of carbohydrates accompanied by delayed glucose absorption, leading to decreased blood glucose levels after meals and thus, inhibition of the enzyme seems to be a crucial strategy for diabetes management and improving overall glycemic control in diabetic patients. The present review article emphasizes the therapeutic promise of recently discovered potential α-amylase inhibitors, highlighting their in vitro, in silico and in vivo profiles. Ultimately, we addressed the contemporary challenges and potential routes ahead in the search for safe and reliable α-amylase inhibitors for clinical use, summarizing the most recent research in the field.

The study of chalcone-1,2,3-triazole hybrids for anticancer activity is quite a recent area of focus, primarily because of the increasing demand for developing new drugs to treat cancer. The chalcones and 1,2,3-triazole rings in hybrid compounds has recently emerged as a promising strategy for developing novel anticancer agents. The 1,2,3-triazole ring, known for its stability and hydrogen bonding capabilities, enhances the target binding affinity of these hybrids. Chalcones possess an α,β-unsaturated carbonyl system crucial for their anticancer activity The synergistic effect of these two moieties results in compounds with potent anticancer properties. This review explores the structure-activity relationship studies which revealed that the electronic and lipophilic properties of substituents on the phenyl rings of chalcones significantly influence their anticancer activity. Electron-donating and electron-withdrawing groups can affect cellular uptake and target engagement. Incorporating various substituents into the 1,2,3-triazole ring can improve selectivity and potency against specific cancer cell lines. These hybrids often exert their anticancer effects through apoptosis and cell cycle disruption. Recent research indicates 1,2,3-triazole chalcone hybrids hold therapeutic promise as anticancer agents. Further optimization through SAR studies and in-depth mechanistic investigations could lead to the development of highly potent and selective anticancer agents with minimal toxicity.

Aim: With the aim of simultaneously modulating the epigenetic system and the protein kinase pathway, we selected the enzyme histone deacetylase (HDAC) and the Rho-associated protein kinases (ROCK) as desired targets to develop potential multitarget anticancer agents with additional antimetastatic properties. We report here the rational design, synthesis, and biological evaluation of the first-in-class HDAC/ROCK multitarget inhibitors in pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast cancer (TNBC).

Materials and methods: A molecular docking study performed with the Gold software was used to develop HDAC/ROCK multitarget inhibitors. IC₅₀ values were determined by enzyme assays. The cytotoxicity, anti-migratory and anti-invasive properties of the inhibitors were evaluated using triple-negative breast cancer cells (MDA-MB-231 and HCC 1973) and pancreatic ductal adenocarcinoma cells (Panc-1 and MiaPaCa-2).

Results: C-9 showed significant inhibition of HDAC6, ROCK1 and ROCK2. At the same time, this compound showed strong antiproliferative effects on MDA-MB-231, MiaPaCa-2 and Panc-1 cell lines with IC₅₀ values of 5.81 μM, 3.87 μM and 19.57 μM. In addition, it demonstrated great anti-invasive and anti-migratory effects.

Conclusion: The findings of this study strongly suggest that the simultaneous inhibition of ROCK and HDACs holds significant potential as a promising therapeutic strategy in the advancement of cancer treatment.