Design, Synthesis and Evaluation of 2,4- Diaminoquinazoline Derivatives as Potential Tubulin Polymerization Inhibitors

Microtubules are highly dynamic polymers composed of α- and β- tubulin proteins that have been shown to be potential therapeutic targets for the development of anticancer drugs. Currently, a wide variety of chemically diverse agents that bind to β- tubulin have been reported. Nocodazole (NZ) and colchicine (COL) are well- known tubulin- depolymerizing agents that have close binding sites in the β- tubulin. In this study, we designed and synthesized a set of nine 2,4- diaminoquinazoline derivatives that could occupy both NZ and COL binding sites. The synthesized compounds were evaluated for their antiproliferative activities against five cancer cell lines (PC- 3, HCT- 15, MCF- 7, MDA- MB- 231, and SK- LU- 1), a noncancerous one (COS- 7), and peripheral blood mononuclear cells (PBMC). The effect of compounds 4- e and 4- i on tubulin organization and polymerization was analyzed on the SK- LU- 1 cell line by indirect immunofluorescence, western blotting, and tubulin polymerization assays. Our results demonstrated that both compounds exert their antiproliferative activity by inhibiting tubulin polymerization. Finally, a possible binding pose of 4- i in the NZ/COL binding site was determined by using molecular docking and molecular dynamics (MD) approaches. To our knowledge, this is the first report of non- N- substituted 2,4- diaminoquinazoline derivatives with the ability to inhibit tubulin polymerization.More is not always better: A set of nine 2,4- diaminoquinazoline derivatives were evaluated for their ability to inhibit tubulin polymerization by using immunofluorescence staining analysis, western blotting, tubulin polymerization assays, and molecular dynamics simulations. Our study provides valuable insights into the design of 2,4- diaminoquiazoline compounds as tubulin polymerization inhibitors for the treatment of lung and breast cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163403/3/cmdc202000185-sup-0001-misc_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163403/2/cmdc202000185_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163403/1/cmdc202000185.pd

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Design, Synthesis and Evaluation of 2,4‐Diaminoquinazoline Derivatives as Potential Tubulin Polymerization Inhibitors

Microtubules are highly dynamic polymers composed of α- and β- tubulin proteins that have been shown to be potential therapeutic targets for the development of anticancer drugs. Currently, a wide variety of chemically diverse agents that bind to β- tubulin have been reported. Nocodazole (NZ) and colchicine (COL) are well- known tubulin- depolymerizing agents that have close binding sites in the β- tubulin. In this study, we designed and synthesized a set of nine 2,4- diaminoquinazoline derivatives that could occupy both NZ and COL binding sites. The synthesized compounds were evaluated for their antiproliferative activities against five cancer cell lines (PC- 3, HCT- 15, MCF- 7, MDA- MB- 231, and SK- LU- 1), a noncancerous one (COS- 7), and peripheral blood mononuclear cells (PBMC). The effect of compounds 4- e and 4- i on tubulin organization and polymerization was analyzed on the SK- LU- 1 cell line by indirect immunofluorescence, western blotting, and tubulin polymerization assays. Our results demonstrated that both compounds exert their antiproliferative activity by inhibiting tubulin polymerization. Finally, a possible binding pose of 4- i in the NZ/COL binding site was determined by using molecular docking and molecular dynamics (MD) approaches. To our knowledge, this is the first report of non- N- substituted 2,4- diaminoquinazoline derivatives with the ability to inhibit tubulin polymerization.More is not always better: A set of nine 2,4- diaminoquinazoline derivatives were evaluated for their ability to inhibit tubulin polymerization by using immunofluorescence staining analysis, western blotting, tubulin polymerization assays, and molecular dynamics simulations. Our study provides valuable insights into the design of 2,4- diaminoquiazoline compounds as tubulin polymerization inhibitors for the treatment of lung and breast cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163403/3/cmdc202000185-sup-0001-misc_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163403/2/cmdc202000185_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163403/1/cmdc202000185.pd

Anti-Diabetic Activity of Glycyrrhetinic Acid Derivatives FC-114 and FC-122: Scale-Up, In Silico, In Vitro, and In Vivo Studies

Type 2 diabetes (T2D) is one of the most common diseases and the 8th leading cause of death worldwide. Individuals with T2D are at risk for several health complications that reduce their life expectancy and quality of life. Although several drugs for treating T2D are currently available, many of them have reported side effects ranging from mild to severe. In this work, we present the synthesis in a gram-scale as well as the in silico and in vitro activity of two semisynthetic glycyrrhetinic acid (GA) derivatives (namely FC-114 and FC-122) against Protein Tyrosine Phosphatase 1B (PTP1B) and α-glucosidase enzymes. Furthermore, the in vitro cytotoxicity assay on Human Foreskin fibroblast and the in vivo acute oral toxicity was also conducted. The anti-diabetic activity was determined in streptozotocin-induced diabetic rats after oral administration with FC-114 or FC-122. Results showed that both GA derivatives have potent PTP1B inhibitory activity being FC-122, a dual PTP1B/α-glucosidase inhibitor that could increase insulin sensitivity and reduce intestinal glucose absorption. Molecular docking, molecular dynamics, and enzymatic kinetics studies revealed the inhibition mechanism of FC-122 against α-glucosidase. Both GA derivatives were safe and showed better anti-diabetic activity in vivo than the reference drug acarbose. Moreover, FC-114 improves insulin levels while decreasing LDL and total cholesterol levels without decreasing HDL cholesterol

Comparison of international normalized ratio audit parameters in patients enrolled in GARFIELD-AF and treated with vitamin K antagonists

Vitamin K antagonist (VKA) therapy for stroke prevention in atrial fibrillation (AF) requires monitoring of the international normalized ratio (INR). We evaluated the agreement between two INR audit parameters, frequency in range (FIR) and proportion of time in the therapeutic range (TTR), using data from a global population of patients with newly diagnosed non-valvular AF, the Global Anticoagulant Registry in the FIELD\u2013Atrial Fibrillation (GARFIELD-AF). Among 17\ua0168 patients with 1-year follow-up data available at the time of the analysis, 8445 received VKA therapy (\ub1antiplatelet therapy) at enrolment, and of these patients, 5066 with 653 INR readings and for whom both FIR and TTR could be calculated were included in the analysis. In total, 70\ua0905 INRs were analysed. At the patient level, TTR showed higher values than FIR (mean, 56\ub70% vs 49\ub78%; median, 59\ub77% vs 50\ub70%). Although patient-level FIR and TTR values were highly correlated (Pearson correlation coefficient [95% confidence interval; CI], 0\ub7860 [0\ub7852\u20130\ub7867]), estimates from individuals showed widespread disagreement and variability (Lin's concordance coefficient [95% CI], 0\ub7829 [0\ub7821\u20130\ub7837]). The difference between FIR and TTR explained 17\ub74% of the total variability of measurements. These results suggest that FIR and TTR are not equivalent and cannot be used interchangeably