Home > Studies on Anticancer and Antileishmanial Potentials of Synthetic Compounds and Insight into Anticancer Mechanism of Selected Organotin Iv Compounds
Studies on Anticancer and Antileishmanial Potentials of Synthetic Compounds and Insight into Anticancer Mechanism of Selected Organotin Iv Compounds
Drug development has multiple stages of drug designing and evaluation in pharmacological models for desired clinical outcomes. The unmet need to completely eradicate cancer and leishmaniasis drives researchers to continue the struggle for safer and effective medicines. Along these lines, a library of 78 organic synthetic compounds including organotin (IV) (39), indoline (15), hydrazide (4), diazole (2) and ferrocene (18) derivatives were studied against Leishmania and cancer using in vitro, in silico and in vivo models. Cytotoxicity against DU145, THP-1 and isolated lymphocytes was shown by 36 (> 70%), 21 (> 50-70%), and 18 (least IC50 2.23 µg/ml) organotins and 1 (75.72%), 4 (50.2-82.3%) and 2 (least IC50 13 µg/ml) indolines, respectively. Only 5 (50.08-81.7%) hydrazides/diazoles and 9 (least IC50 6.66 µg/ml) ferrocenes were cytotoxic to THP-1 cells and lymphocytes, respectively. A total of 38 (least MIC 0.0122 µg/disc) organotins, 1 (least MIC 3.125 µg/disc) indoline, 3 (least MIC 1.5625 µg/disc) diazole/hydrazides and 17 (least MIC 0.74 µg/disc) ferrocenes demonstrated protein kinase (PK) inhibition activity in Streptomyces 85E. Next, in silico analysis of selected 36 organotin (IV) compounds, comparatively more cytotoxic to cancer cells, showed that these were druglike to mid structures, have low to high blood brain barrier penetration and human intestinal absorption (caco2 cell permeability 17.6-35.09 nm/sec) and were metabolized by phase I and phase II reactions. Organotins were also predicted to target multiple enzymes, transcription factors, receptors, transporters, ion channels and other proteins. Subsequently, in vitro cytotoxicity analysis in prostate cancer cell lines and fibroblasts provided least IC50 values of 0.17 µM (PC3M) and 1.67 µM (fibroblasts) for triphenyltin (IV); 0.63 µM (PC3M) and 0.12 µM (fibroblasts) for tributyltin (IV); 0.33 µM (PC3M) and 2.55 µM (fibroblasts) for dibutyltin (IV) and 6.06 µM (PC3M) and 4.29 µM (fibroblasts) for tribenzyltin (IV) compounds after 72 h of treatment. Eventually, in-depth study of two most active compounds namely dibutylstannanediyl (2Z,2’Z)-bis(4(benzylamino)-4-oxobut-2-enoate (Ch-620) and triphenylstannyl 2-(benzylcarbamoyl) benzoate (Ch-319), showed that both compounds were more cytotoxic to prostate cancer and melanoma cells as compared to normal cells, restricted their colony forming capacity and migration, induced cell cycle arrest and caspase mediated apoptosis and disrupted associated regulatory proteins. Ch-620 resulted in phosphorylation of p38 MAPK and ERK1/2, upregulation of PPARα, decreased expression of SMAD4 and ITGB5 and reduced tumor proliferation as observed by proteomics, in vitro and in vivo xenograft studies. Treatment of cancer cells and transgenic Pten knockout mice with Ch-319 downregulated PI3K/Akt signaling associated with elevation of FOXO3a expression. In addition, Ch-319 decreased expression of epithelial-mesenchymal transition markers Ncadherin and Vimentin with concomitant increase in E-cadherin in in vitro. Immunohistochemical examination of tumor sections also depicted reduction of proliferation markers. Moreover, evaluation of 78 compounds against Leishmania tropica kwh showed that 37, 5 and 1 organotin, indoline and ferrocene compounds, respectively inhibited growth of promastigotes. The selected 43 compounds predominantly organotin (IV) derivatives, halted the growth of Leishmania promastigotes partially by producing reactive oxygen species. Antileishmanial activity was reduced by 4.1-6.9 and 1.4-7.96% in triphenyltin (IV), 3.3-14.22 and 6.3-11.2% in tribenzyltin (IV), 5.2-34.38 and 1.838.2% in tributyltin (IV) and 7.9-15.7 and 5.2-15.4% in dibutyltin (IV) compounds in the presence of sodium azide and mannitol, respectively. Indolines and ferrocenes demonstrated antileishmanial activity reduction maximally in the presence of mannitol by 5.3 and 6.22%, respectively. Considering all these results, it is proposed that Ch-319 and Ch-620 have potential to be developed as anticancer agents against prostate cancer. Furthermore, organotin (IV) compounds in particular are also potent antileishmanial agents and detailed analysis on their mechanism is recommended.
تیرا سوہنا پاک خیال رہندا ہر دم میرے نال اندروں باہروں جو ہِک ہوون اوہ بندے نیں خال خال اثر نسل تک جاری رہندا جیہڑا ہووے حرام دا مال عاشق تپ جد کندن ہووے ہکو جئے نیں ہجر وصال روندے روندے سو جاندے نیں ڈھیر غریباں دے کئی بال سار نہ پچھی یار سجن نے گزرے کتنے ماہ و سال
Allah Almighty sent prophets for guidance of human beings and revealed the books on them, who strove for transformation of the society. Islam declared that master and salve, king and subjects, men and women, all are equal and slaves of God. They are equal before the Law. The Holy Prophet (PBUH) said ‘‘All human beings have equal rights’’. The Holy Prophet maintained religious equality. He did not talk ill of other religious faiths, rather he protected the rights and prosperity of non-Muslims who lived in Islamic society. The Holy Prophet (PBUH) preached goodness among humans like truth and compassion. He also restricted them from vice like lie, betray, greed, pride, bribery and domestic evils. For being the last Ummah, the Holy Quran entrusted the Muslims with the mission of calling others to goodness and stopping them from the evil. This Paper attempts the role of Islamic teachings the transformation of the society.
In last few decades, it has been proved that fractional order differential equations and their systems are very important in mathematical modeling various phenomena of biological, chemical and physical sciences. In addition to these, a fractional calculus also contains many applications in various fields of engineering and technology. For this propose , differential equations of fractional order is the point of attention in last few years. This project is related with the study of existence theory and numerical solutions of fractional order differential equations. For this study, we first review some useful definitions, notations and results from fractional calculus. Also for the study of numerical solutions, we use a power full techniques. We start our thesis with the study of existence and uniqueness of positive solutions for simple boundary value problem. Then, we obtain necessary and sufficient conditions for existence of at least three positive solutions for the considered models. To solve coupled systems of nonlinear fractional differential equations, we discussamethodwhichisknownasLaplaceAdomiandecompositionmethod(LADM). LADM is an excellent mathematical tool for solving linear and nonlinear differential equations. This method is a combination of the famous integral transform known as Laplace transform and the Adomain decomposition method. In this method, we handle some class of coupled systems of nonlinear fractional order differential equations. Using the proposed method to obtain successfully an exact or approximate solution in the form of convergence series. Thus, we can easily applyLADMto solveawideclassof nonlinearfractionalorderdifferentialequations.The suggested method is applied without any linearization, discretization and unrealistic assumptions. It has been proved that LADM is vary efficient and suitable to solve non-linear problem of physical nature. Some examples are presented to justify the accuracy and performance of the proposed method.