Discovery of new quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors and their anticancer activities - Part 1.

Overexpression of EGFR and HER2 are observed in many breast, ovarian, colon and prostate cancers. The second and third generation irreversible EGFR/HER2 dual kinase inhibitors became popular after the approval of Afatinib by FDA to overcome the mutation related problem. To find efficacious drug candidates, a series of novel quinazoline derivatives were designed, synthesized and evaluated as dual EGFR/HER2 tyrosine kinase (TK) inhibitors. Selected twenty four compounds were reported here with significant inhibitory activities against EGFR/HER2 tyrosine kinases. Several compounds showed nanomolar IC50 values. In vitro studies of quinazoline derivatives were done on NCI-H1975, HCC827, A431, MDA MB-453 cell lines. The compounds 1a, 1d and 1v were found more potent compared to standard drug afatinib. In vivo efficacy study of 1d on nude mice NCI-H1975 tumour xenograft model was discussed.

Cardiovascular protection with danshensu in spontaneously hypertensive rats.

The objective of the present study was to evaluate the cardiovascular protective effects of Danshensu, a water-soluble active component of Danshen, in spontaneously hypertensive rats (SHR). SHR (male, 9 weeks old, n=30) were divided into three groups: 1) saline control (n=10); 2) a Danshensu (10 mg/kg/d, intraperitoneally (i.p.)) treatment group (n=10); and 3) a Valsartan (10 mg/kg/d, intragastrically (i.g.)) treatment group (n=10). Age-matched Wistar-Kyoto rats (n=10) were used as normotensive controls. Saline and drug treatments were administered for 6 weeks. When the rats were 15 weeks old, their hearts were excised and arrhythmias were induced by an ex vivo ischemia/reperfusion protocol. The heart weight to body weight index was significantly increased in SHR, and this increase was attenuated with Danshensu treatment (both p<0.05). Systolic blood pressure and diastolic blood pressure were also decreased with Danshensu treatment, from 145±3 and 103±10 mmHg to 116±7 and 87±2 mmHg in SHR and Danshensu-treated groups, respectively (both p<0.05). The incidences of ventricular tachycardia and ventricular fibrillation decreased from 100 to 50% and 30% in SHR, respectively, with Danshensu treatment (both p<0.05). Serum nitric oxide content and inducible nitric oxide synthase activity were significantly increased with Danshensu (both p<0.05). In addition, Danshensu increased the K(+) current density and Ca(2+) activated K(+) channel current density of mesenteric vascular smooth muscle cells isolated from SHRs. Together, these results demonstrate that Danshensu imparts cardiovascular protection by modifying vascular responses during the progression of hypertension.

Antioxidant and cardioprotective effects of Danshensu (3-(3, 4-dihydroxyphenyl)-2-hydroxy-propanoic acid from Salvia miltiorrhiza) on isoproterenol-induced myocardial hypertrophy in rats.

Myocardial hypertrophy has been linked to the development of a variety of cardiovascular diseases, and is a risk factor for myocardial ischemia, arrhythmias, and sudden cardiac death. The objective of the present study was to evaluate the cardioprotective effects of Danshensu (DSS), a water-soluble active component of Danshen, on cardiac hypertrophy in rats. We are the first to report that DSS reversed Cx43 down-regulation in ventricular tissue. Cardiomyopathy in rats was produced using isoproterenol (Iso) treatment (2.5 mg/kg/d, s.c.) for seven days. DSS (3 and 10 mg/kg/d, i.p.) and Valsartan (Val) (10 mg/kg, i.g.) were administered on days 4-7 of Iso-treatment. Heart weight index, hemodynamic parameters, and ECG II parameters were monitored and recorded; protein expression of left ventricular connexin 43 (Cx43) and the activity of the redox system were assayed, and arrhythmias were produced using a coronary ligation/reperfusion procedure. The results demonstrated that DSS treatment significantly decreased heart weight/body weight (HW/BW) and left ventricular weight/body weight (LVW/BW) ratios. The protective role of DSS against Iso-induced myocardial hypertrophy was further confirmed using ECG. The incidences of ventricular tachycardia and ventricular fibrillation (VT, VF) and arrhythmic scores were higher in the model group and were suppressed by DSS. DSS decreased the serum and myocardium levels of creatine kinase, lactate dehydrogenase, and malondialdehyde (CK, LDH, and MDA) and increased serum activity of superoxide dismutase (SOD) in a dose-dependent manner. Cx43 expression in the left ventricle was down-regulated, and there was significant oxidative stress in this model of cardiomyopathy. DSS reversed the down-regulated Cx43 protein levels and showed potent anti-oxidative activities and cellular protection. These data demonstrate that DSS can prevent cardiac I/R injury and improve cardiac function in a rat model of hypertrophy, the effects partially resulting from antioxidants and the protection from Cx43 expression.