Search

Increasing the levels of antiapoptotic Bcl-2 proteins is an important way that cancer cells utilize to get out of apoptosis, underscoring their significance as promising targets for anticancer therapies. Lately, a primary compound 1 bearing thiazolidine-2,4-dione was discovered to exhibit comparable Mcl-1 inhibitory activity in comparison to WL-276. Herein, thirty-nine thiazolidine-2,4-dione analogs were yielded through incorporating different biphenyl moieties (R 1 ), amino acid side chains (R 2 ) and sulfonamides (R 3 ) on 1. The findings indicated that certain compounds exhibited favorable inhibitory effects against Bcl-2/Mcl-1, while demonstrating limited or negligible binding affinity towards Bcl-xL. In particular, compounds 16 and 20 exhibited greater Bcl-2/Mcl-1 inhibition compared to AT-101, WL-276 and 1. Moreover, they demonstrated notable antiproliferative effects and significantly induced apoptosis in U937 cells. The western blot and co-immunoprecipitation assays confirmed that 20 could induce alterations in the expression of apoptosis-associated proteins to result in apoptosis through on-target Bcl-2 and Mcl-1 inhibition. In addition, 20 exhibited favorable stability profiles in both rat plasma and rat liver microsomes. In total, 20 could be used as a promising compound to discover Bcl-2/Mcl-1 dual inhibitors with favorable therapeutic properties., Competing Interests: 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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Currently, the arise of drug resistance and undesirable off-target effects of anti-cancer agents are major challenges for cancer treatment, which energizes medicinal chemists to develop more anti-cancer agents with high efficiency and low toxicity continuously. Sulfonamide derivatives are a class of promising compounds with diverse biological activities including anti-cancer, and parts of them have been marketed for cancer therapy, such as Belinostat, ABT-199 and Amsacrine. In this review, we summed up the recent advances of sulfonamide derivatives as potential anti-cancer agents based on the anti-cancer targets, such as aromatase, carbonic anhydrase (CA), anti-apoptotic B-cell lymphoma-2 (Bcl-2) proteins, topoisomerase and phosphatidylinositol 3-kinase (PI3K), and elucidated the corresponding structure-activity relationships (SARs) of most sulfonamide derivatives. We hope this review could provide a clear insight for medicinal chemists in the rational design of more potent and bio-target specific anti-cancer agents., Competing Interests: 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., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Cancer has been the second heath killer being next only to cardiovascular diseases in human society. Although many efforts have been taken for cancer therapy and many achievements have been yielded in the diagnosis and treatment of cancer, the current first-line anti-cancer agents are insufficient owing to the emergence of multi-drug resistance and side effects. Therefore, it is urgent to develop new anti-cancer agents with high activity and low toxicity. 2-Aminothiazole is a class of important scaffold which widely distributes in many natural and synthetic compounds with many pharmacological effects including the potential anti-cancer activity. In this review, we summarized the recent progress of 2-aminothiazole as a privileged scaffold for the discovery of anti-cancer agents based on biological targets, such as tubulin protein, histone acetylase/histone deacetylase (HAT/HDAC), phosphatidylinositol 3-kinases (PI3Ks), Src/Abl kinase, BRAF kinase, epidermal growth factor receptor (EGFR) kinase and sphingosine kinase (SphK), and also investigated the structure-activity relationships (SARs) of most compounds. It is believed that this review could be helpful for medicinal chemists in the discovery of more anti-cancer agents bearing 2-aminothiazole scaffold with excellent activity and high therapeutic index., Competing Interests: Declaration of competing interest We declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Overexpressing myeloid cell leukemia sequence 1 (Mcl-1) protein is an important way to confer the resistance of cancer cells to conventional anti-cancer treatments. Therefore, developing Mcl-1 inhibitors has become an attractive strategy for cancer therapy. In the studies, a series of new indazole-acylsulfonamide hybrids were designed, synthesized and evaluated as potent Mcl-1 inhibitors. Among them, the most potent compound 17 (K i  = 0.43 μM) showed a little better inhibitory activity against Mcl-1 protein than positive control AT-101 (K i  = 0.45 μM). Pleasingly, it displayed > 40-fold selectivity over Bcl-2 (K i  = 18 μM) and Bcl-xL (no activity). Furthermore, compound 17 had good inhibitory activities against PC-3, MDA-MB-231 and K562 cells (IC 50  = 12.3, 10.6 and 6.62 μM, respectively) and could effectively induce apoptosis and the activation of caspase-3 in a dose-dependent manner in K562 cells., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Lung cancer is the leading cause of cancer mortality worldwide. Drug resistance is the major barrier for the treatment of non-small cell lung cancer (NSCLC). The aim of this research is to develop an aptamer-decorated hybrid nanoparticle for the co-delivery of docetaxel prodrug (DTXp) and cisplatin (DDP) and to treat lung cancer., Materials and Methods: Aptamer-conjugated lipid-polymer ligands and redox-sensitive docetaxel prodrug were synthesized. DTXp and DDP were loaded into the lipid-polymer hybrid nanoparticles (LPHNs). The targeted efficiency of aptamer-decorated, DTXp and DDP co-encapsulated LPHNs (APT-DTXp/DDP-LPHNs) was determined by performing a cell uptake assay by flow cytometry-based analysis. In vivo biodistribution and anticancer efficiency of APT-DTXp/DDP-LPHNs were evaluated on NSCLC-bearing mice xenograft., Results: APT-DTXp/DDP-LPHNs had a particle size of 213.5 ± 5.3 nm, with a zeta potential of 15.9 ± 1.9 mV. APT-DTXp/DDP-LPHNs exhibited a significantly enhanced cytotoxicity (drug concentration causing 50% inhibition was 0.71 ± 0.09 μg/mL), synergy antitumor effect (combination index was 0.62), and profound tumor inhibition ability (tumor inhibition ratio of 81.4%) compared with the non-aptamer-decorated LPHNs and single drug-loaded LPHNs., Conclusion: Since the synergistic effect of the drugs was found in this system, it would have great potential to inhibit lung tumor cells and in vivo tumor growth., Competing Interests: Ruifeng Wu and Zhiqiang Zhang are co-first authors. The authors report no conflicts of interest in this work., (© 2020 Wu et al.)

Lung cancer remains the leading cause of cancer associated deaths worldwide. Compared with traditional chemotherapy for non-small cell lung cancer (NSCLC), specific targeted therapies are better choices for advanced patients to improve their survival. In this study, we attempted to fabricate Nitroimidazoles (NI) and Hyaluronic acid (HA) co-decorated, cisplatin (DDP) loaded polymeric nanoparticles (PNPs) (NI/HA-DDP-PNPs) and lipid-polymer hybrid nanoparticles (LPNs) (NI/HA-DDP-LPNs) for the facilitated drug delivery at lung tumor regions (hypoxic regions). In vitro cytotoxicity and cellular uptake; In vivo anti-tumor activity and in vivo tissue biodistribution of PNPs and LPNs were evaluated and compared in lung carcinoma cells and xenograft. Hydrodynamic size of NI/HA-DDP-LPNs was 185.6 ± 4.7 nm, which is larger than that of NI/HA-DDP-PNPs (136.7 ± 3.5 nm). The zeta potential of NI/HA-DDP-PNPs (-31.2 ± 2.7 mV) was more negative than NI/HA-DDP-LPNs (-22.3 ± 2.1 mV). The peak plasma concentration (C max ) achieved from NI/HA-DDP-PNPs and NI/HA-DDP-LPNs was 35.2 ± 1.6 and 37.3 ± 1.7 μg/mL. The half-life (T 1/2 ) of NI/HA-DDP-PNPs and NI/HA-DDP-LPNs was 12.03 ± 0.75 and 11.78 ± 0.89 h. Area Under Curve (AUC) of NI/HA-DDP-PNPs and NI/HA-DDP-LPNs showed no significant difference while greater than other groups. NI/HA-DDP-LPNs exhibited excellent antitumor effect against drug-resistant human lung cancer A549/DDP cells in vitro and in vivo, better than that of NI/HA-DDP-PNPs. Considering that the low toxicity of NI/HA-DDP-LPNs and NI/HA-DDP-PNPs, NI/HA-DDP-LPNs could be a more promising system for lung cancer targeted therapy., Competing Interests: Declaration of Competing Interest The author reports no conflicts of interest in this work., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

In general, heterocyclic compounds are a significant source of pharmacologically active compounds. Among them, the indole scaffold widely distributes in natural products and bioactive molecules including anti-cancer agents. In view of its unique physic-chemical and biological properties, it has been used as a privileged scaffold in the anti-cancer agents design. So far, many natural and synthetic indole derivatives have been discovered as promising anti-cancer agents used in clinic or clinical evaluations, suggesting its prominent place in anti-cancer drugs development. This review aimed to provide a clear knowledge on the recent development of indoles as anti-cancer agents, such as myeloid cell leukemia-1 (Mcl-1) inhibitors, proviral insertion site in moloney murine leukemia virus (Pim) inhibitors, histone deacetylase (HDAC) inhibitors, silent mating type information regulation 2 homolog (SIRT) inhibitors and tubulin inhibitors, and made an insight into the corresponding structure-activity relationships (SARs). We hope the review could give a guide to develop new anti-cancer agents with greater potency against drug-sensitive and drug-resistant cancers in the future., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

The anti-apoptotic members of B-cell lymphoma-2 (Bcl-2) proteins family, such as Bcl-2 and myeloid cell leukemia-1 (Mcl-1), are the key regulators of the intrinsic pathway of apoptosis and overexpressed in many tumor cells, which have been confirmed as potential drug targets for cancers. A number of Bcl-2 proteins inhibitors have been developed and conducted clinical trials, but no Mcl-1 inhibitors are presented in the clinics. In addition, Mcl-1 is an important reason for the resistance to radio- and chemotherapies, including inhibitors that target other Bcl-2 family members. For example, the recently launched Bcl-2-selective inhibitor ABT-199 displays highly potency in the treatment of chronic lymphocytic leukemia (CLL), but it cannot induce the apoptosis controlled by Mcl-1 in some tumor cell lines. Therefore, developing potent Mcl-1 inhibitors become urgently needed in clinical therapy. This review briefly introduces the structure of Mcl-1 protein, the role in cancers and focuses on the progress of small-molecule Mcl-1 inhibitors from 2012 to 2017., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Currently, cancer continues being a dramatically increasing and serious threat to public health. Although many anti-tumor agents have been developed in recent years, the survival rate of patients is not satisfactory. The poor prognosis of cancer patients is closely related to the occurrence of drug resistance. Therefore, it is urgent to develop new anti-tumor agents to make up for the deficiency. Indazoles is an important class of heterocyclic compounds possessing a variety of biological activities, such as anti-tumor, anti-bacterial, antiinflammatory, anti-depressant and anti-hypertensive. This review focuses on the recent research advances of indazole derivatives in the aspect of anti-tumor., Methods: We have searched the recent literatures about indazole derivatives from the online resources and databases, such as pubmed, scifinder and google scholar., Results: In the recent years, many efforts have been taken to develop indazole derivatives as fibroblast growth factor receptor (FGFR) inhibitors, indoleamine-2,3-dioxygenase1 (IDO1) inhibitors, proviral integration site MuLV (Pim) kinase inhibitors, aurora kinases inhibitors, Bcr-Abl inhibitors, hypoxia inducible factor-1 (HIF-1) inhibitors and carbonic anhydrase (CA) inhibitors. Most compounds display good anti-tumor activities., Conclusion: Developing new anti-cancer agents with new scaffolds and high efficiency is a big challenge for researchers. Indazole derivatives are a class of important bioactive compounds. Making structural modifications on active indazole derivatives according to the corresponding structure-activity relationships is of benefit to obtain more potent anti-cancer leads or clinical drugs. This review will be useful for further development of new indazole-based derivatives as anti-cancer agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Inspired by antitumor drug 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX), a series of novel nitrobenzoxadiazole-piperazine hybrids were designed, synthesized, and evaluated for their anticancer activities in vitro. The representative hybrids 3u , 3v , and 3w containing a chloromethyl substitution exhibited the most potent anticancer effects against MCF-7, HepG2, and A549 cells. Among the synthesized compounds, 3u was found to be the most active derivative possessing broad-spectrum cytotoxicity against HepG2 and A549 cells with the highest IC 50 values of 3.50 and 4.73 μM, respectively. Mechanistic studies of anti-proliferative activity revealed that compound 3u triggered apoptosis in cancer cell lines through hydrolyzing of PARP by caspase 3, and effectively inhibited colony formation. These results suggested that compound 3u deserves further development as a promising lead compound for discovering novel antitumor agents. [Display omitted] • Novel nitrobenzoxadiazole-piperazine conjugates were designed and synthesized. • Compound 3v , 3w , and 3x showed the most excellent broad-spectrum cytotoxic activity. • Anticancer potential of compound 3v was positively correlated with the expression of apoptosis-related proteins cleaved-PARP and cleaved - caspase 3. [ABSTRACT FROM AUTHOR]