Current development of pyrazole-azole hybrids with anticancer potential.

Chemotherapy is a critical treatment modality for cancer patients, but multidrug resistance remains one of the major challenges in cancer therapy, creating an urgent need for the development of novel potent chemical entities. Azoles, particularly pyrazole, could interact with different biological targets and exhibit diverse biological properties including anticancer activity. Many clinically used anticancer agents own an azole moiety, demonstrating that azoles are privileged and pivotal templates in the discovery of novel anticancer chemotherapeutics. The present article is an attempt to highlight the recent advances in pyrazole-azole hybrids with anticancer potential and discuss the structure-activity relationships, covering articles published from 2018 to present, to facilitate the rational design of more effective anticancer candidates.

The current scenario on anticancer activity of artemisinin metal complexes, hybrids, and dimers.

Cancer, the most significant cause of morbidity and mortality, has already posed a heavy burden on health care systems globally. In recent years, cancer treatment has made a significant breakthrough, but cancer cells inevitably acquire resistance, and the efficacy of the treatment is greatly reduced as the tumor progresses. To overcome the above issues, novel chemotherapeutics are needed urgently. Artemisinin and its derivatives-sesquiterpene lactone compounds possessing a unique peroxy bridge moiety-exhibit excellent safety and tolerability profiles. Mechanistically, artemisinin derivatives can promote cancer cell apoptosis, induce cell cycle arrest and autophagy, and inhibit cancer cell invasion and migration. Accordingly, artemisinin derivatives demonstrate promising anticancer efficacy both in vitro and in vivo, and even in clinical Phase I/II trials. The purpose of the present review article is to provide an emphasis on the current scenario (January 2017-January 2022) of artemisinin derivatives with potential anticancer activity, inclusive of artemisinin metal complexes, hybrids, and dimers. The structure-activity relationships and mechanisms of action are also discussed to facilitate the further rational design of more effective candidates.

Design, synthesis, and molecular docking study of 3H-imidazole[4,5-c]pyridine derivatives as CDK2 inhibitors.

A novel series of imidazo[4,5-c]pyridine-based CDK2 inhibitors were designed from the structure of CYC202 via scaffold hopping strategy. These compounds were synthesized and biologically evaluated for their CDK2 inhibitory and in vitro anti-proliferation potential against cancer cell lines. Several compounds exhibited potent CDK2 inhibition with IC50 values of less than 1 µM. The most potent compound 5b showed excellent CDK2 inhibitory (IC50 = 21 nM) and in vitro anti-proliferation activity against three different cell lines (HL60, A549, and HCT116). The molecular docking and dynamic studies portrayed the potential binding mechanism between 5b and CDK2, and several key interactions between them were observed, which would be the reason for its potent CDK2 inhibitory and anti-proliferation activities. Therefore, the pyridin-3-ylmethyl moiety would serve as an excellent pharmacophore for the development of novel CDK2 inhibitors for targeted anti-cancer therapy.

Nine-month angiographic and two-year clinical follow-up of novel biodegradable-polymer arsenic trioxide-eluting stent versus durable-polymer sirolimus-eluting stent for coronary artery disease.

BACKGROUND: Despite great reduction of in-stent restenosis, first-generation drug-eluting stents (DESs) have increased the risk of late stent thrombosis due to delayed endothelialization. Arsenic trioxide, a natural substance that could inhibit cell proliferation and induce cell apoptosis, seems to be a promising surrogate of sirolimus to improve DES performance. This randomized controlled trial was to evaluate the efficacy and safety of a novel arsenic trioxide-eluting stent (AES), compared with traditional sirolimus-eluting stent (SES). METHODS: Patients with symptoms of angina pectoris were enrolled and randomized to AES or SES group. The primary endpoint was target vessel failure (TVF), and the second endpoint includes rates of all-cause death, cardiac death or myocardial infarction, target lesion revascularization (TLR) by telephone visit and late luminal loss (LLL) at 9-month by angiographic follow-up. RESULTS: From July 2007 to 2009, 212 patients were enrolled and randomized 1:1 to receive either AES or SES. At 2 years of follow-up, TVF rate was similar between AES and SES group (6.67% vs. 5.83%, P = 0.980). Frequency of all-cause death was significantly lower in AES group (0 vs. 4.85%, P = 0.028). There was no significant difference between AES and SES in frequency of TLR and in-stent restenosis, but greater in-stent LLL was observed for AES group (0.29 ± 0.52 mm vs. 0.10 ± 0.25 mm, P = 0.008). CONCLUSIONS: After 2 years of follow-up, AES demonstrated comparable efficacy and safety to SES for the treatment of de novo coronary artery lesions.

Short-term safety and efficiency of cryoablation for renal sympathetic denervation in a swine model.

BACKGROUND: Renal sympathetic nerves are involved in the reflective activation of the sympathetic nervous system in circulatory control. Catheter-based renal denervation (RDN) ameliorated treatment-resistant hypertension safely, but 10%-20% of treated patients are nonresponders to radiofrequency denervation. The purpose of this study was to investigate the safety and efficiency of cryoablation for sympathetic denervation in a swine model and to explore a new way of RDN. METHODS: Seven swines randomly assigned to two groups: Renal cryoablation (CR) group and control group. The control group underwent renal angiogram only. The CR group underwent renal angiogram plus bilateral renal cryoablation. Renal angiograms via femoral were performed before denervation, after denervation and prior to the sacrifice to access the diameter of renal arterial and the pressure of aorta abdominalis. Euthanasia of the swine was performed on 28-day to access norepinephrine (NE) changes of the renal cortex and the changes of renal nerves. RESULTS: Cryoablation did not induce severe complications at any time point. There was no significant change in diameter of renal artery. CR reduced systolic blood pressure (BP) from 145.50 ± 9.95 mmHg at baseline to 119.00 ± 14.09 mmHg. There was a slight but insignificant decrease in diastolic BP. The main nerve changes at 28-day consisted of necrosis with perineurial fibrosis at the site of CR exposure in conjunction with the nerve vacuolation. Compared with the control group, renal tissue NE of CR group decreased by 89.85%. CONCLUSIONS: Percutaneous catheter-based cryoablation of the renal artery is safe. CR could effectively reduce NE storing in the renal cortex, and the efficiency could be maintained 28-day at least.

[Intravascular ultrasound assessment of chitosan/heparin layer-by-layer self assembly coating stent on late stent malapposition and vessel remodeling in porcine model].

OBJECTIVE: To investigate late stent malapposition or vessel remodeling post chitosan/heparin layer-by-layer self assembly coating stent (LBL) implantation in porcine. METHODS: A total of 32 stents [bare metal stent (BMS, n = 9), sirolimus-eluting stent (SES, n = 11) and LBL (n = 12)] were implanted into coronary arteries of 16 porcine. Intravascular ultrasound (IVUS) was performed immediately after stenting and at 1 month after stenting to measure vessel area (VA), stent area (SA) and lumen area (LA). Neointima area (NA) was measured at 1 month post stenting by IVUS to detect signs of stent malapposition and to determine remodeling index (RI). Histopathology was performed at 1 month post stenting to observe vessel wall structure and stent malapposition status. RESULTS: No sign of stent malapposition was detected, VA and SA/LA were similar among groups immediately after stent implantation. At 1 month follow-up, none of three groups showed stent malapposition. VA, SA, NA and LA were (7.30 ± 0.77), (6.83 ± 0.76), (1.40 ± 0.96) and (5.43 ± 0.88) mm(2) in LBL group, (7.13 ± 0.69), (6.63 ± 0.71), (0.28 ± 0.35) and (6.34 ± 0.89) mm(2) in SES group, (7.48 ± 0.70), (7.00 ± 0.52), (2.69 ± 1.58) and (4.31 ± 1.28) mm(2) in BMS group. VA and SA were similar among groups (all P > 0.05). LA in LBL group was smaller than SES group (P < 0.01) and significantly larger than in BMS group (P < 0.05).NA in LBL group was larger than SES group (P < 0.01) and significantly smaller than in BMS group (P < 0.05).RI in LBL, SES and BMS groups was 0.95 ± 0.07, 1.02 ± 0.04 and 0.98 ± 0.04 (P > 0.05). CONCLUSIONS: There is no late stent malapposition or abnormal remodeling post LBL, SES and BMS implantation up to 1 month in this porcine model. LA in LBL group is smaller than SES group and larger than BMS group at 1 month after implantation in this porcine model.

Safety and efficacy of cobalt chromium alloy based sirolimus-eluting stent with bioabsorbable polymer in porcine model.

BACKGROUND: First generation drug-eluting stents (DESs) were based on 316L stainless steel and coated with a permanent polymer. The vessel wall of these DESs was inflammatory and late in-stent thrombosis was reported. Hence, cobalt chromium based DES coated with a bioabsorbable polymer was an alternate choice. METHODS: Cobalt chromium based DES with bioabsorbable polymer (Simrex stent) as well as control stents (Polymer stent and EXCEL(TM) stent) were implanted into porcine arteries. At a designated time, angiography, quantitative coronary angiography (QCA) analysis, histomorphometry, and electron-microscopical follow-up were performed. RESULTS: A total of 98 stents of all the three groups were harvested. At week 24, percent diameter stenosis (%DS), late loss (LL), and percent area stenosis (%AS) of Simrex was (12.9 ± 0.4)%, (0.35 ± 0.02) mm, and (24.5 ± 4.2)%, respectively, without significant difference in comparison to commercialized EXCEL(TM) stent. Slight inflammatory reaction was seen around the stent strut of Simrex, just as in the other two groups. Electron-microscopical follow-up suggested that it might take 4 - 12 weeks for Simrex to complete its re-endothelialization process. CONCLUSIONS: Cobalt chromium based, bioabsorbable polymer coated sirolimus-eluting stent showed excellent biocompatibility. During 24 weeks observation in porcine model, it was proved that this novel DES system successfully inhibited neointima hyperplasia and decreased in-stent stenosis. It is feasible to launch a clinical evaluation to improve the current prognosis of DES implantation.