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 drug-like 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 N-cadherin 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 1.8-38.2% 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.
مولوی عبدالمجید افسوس ہے کہ گذشتہ ۲۰؍ دسمبر کو مولانا عبدالماجد صاحبب دریا بادی کے بڑے بھائی مولوی عبدالمجید صاحب رٹائرڈ ڈپٹی کلکٹر نے انتقال کیا، مرحوم بڑے دیندار اور بڑی خوبیوں کے بزرگ تھے، گو دارالمصنفین سے ان کا کوئی قانونی تعلق نہ تھا لیکن اس کے بڑے مخلص اور پرانے قدر دانوں میں تھے، اس کے کارکنوں سے دوستانہ اور عزیزانہ تعلق رکھتے تھے، مرحوم کو قومی کاموں سے بھی دلچسپی تھی اور مختلف اوقات میں وہ لکھنؤ کے مختلف قومی و تعلیمی اداروں کی اعزازی خدمت انجام دیتے رہے، طبعاً بڑے شریف اور وضعدار تھے، اﷲ تعالیٰ مرحوم کو اپنی رحمت و مغفرت سے سرفراز فرمائے۔ (شاہ معین الدین ندوی،جنوری ۱۹۶۱ء)
Islamic leadership is defined as a divine trust (amanah) from Allah, based on the Tauhidic paradigm of oneness of Allah that is focusing to serve HIM as HIS servant, while at the same time be the servant of Allah, perform the role of Khalefah (vicegerent) of Allah fully adheres to the Sunnah central to Islamic personality, characteristics and aklaq (Islamic moral and ethical) that was exemplified by the prophet (s.a.w), leading followers to the organization goals and to the straight path of the success in the Hereafter. It is based on this adopted definition that the paper tries to look into the notion from perspective of a Malaysian Muslim Philosopher to the core, Syed Muhammad Naquib Al-Attas, who believes in delivering amanah given to him, and at the same time perform the role of vicegerent of Allah. He suggests that lack of good leaders or rise of unqualified and false ones is one of the major problems of Ummah. Content analysis approach is engaged on both primary and secondary data collected. That is to say, it is a qualitative research in nature. The finding shows that the basis of Al-Attas’s concept of leadership is entrenched in Al-Qur’an and the tradition of the prophet in addition to his deep understanding on the Islamic Sciences such as Islamic theology, philosophy, and metaphysis and so on.
The present work is concerned with the determination of blood parameters, enzyme levels, blood chemistry and pesticide residues in the blood samples from different areas of Karachi in comparison with unexposed persons (i.e., control). Total 45 persons (exposed to pesticides) were taken in this study to assay the pesticides residues in their blood and also observed the morphological and chemical changes in the blood of affected persons. From 45 persons, only 20 persons were found positive and included in the study. Out of ten (10) standard pesticides five differentpesticides were identified in the blood of exposed persons such as cypermethrin, deltamethrin, polytrin-C, malathion and permethrin. The other standard pesticides such as DDE, DDT, match, diazinon and monocrotophos were not detected. In addition blood samples were also collected from ten (10) normal persons (not exposed to pesticides) for the determination of blood parameters, enzymes levels and blood chemistry. Regarding blood parameters approximately all the blood samples had significant variations i.e., (increase or decrease level) possibly due to the cumulative effect of pesticide residues e.g., Majid a young male aged 25 years had been exposed to pesticides for long time and therefore his TLC and platelet counts were found high in addition to low levels of RBC count, Hb, Hct and MCH which probably due to the excessive secretion of enzymes. Similarly, Ghulam Hussain another young male person aged only 08 years had low levels of RBC, Hb, Hct, platelet, MCV and MCH, which may be due to toxic effects of pesticides. In differential leukocyte count (DLC), granulocyte count was found in lower limits in 40 samples and showed normal limits in 05 samples. Lymphocyte count was xi found high in 31 samples. Low limit of lymphocyte was not found in any person. Similarly, monocyte count was found in high limits in 38 samples. Low monocyte count was not noted in any sample and the rest of the samples had normal limits of monocyte. Positive effects of pesticide residues were also observed on the enzyme levels. Regarding enzyme levels GPT, ALP, and ɣ - GT had higher levels in maximum number of samples. Cholinesterase was found high in 6 samples out of 45 samples and the highest was found in case of Farhan and Abdul Rahmanwhere as low limit of cholinesterase was noted in 15 samples out of total samples which may due to prolonged exposure of pesticides. GPT was found in high limits in all the samples. Also ɣ - GT and ALP found high in all the samples. Effect of pesticide residues were also observed on the blood chemistry. Regarding total bilirubin only one sample showed normal limit. The rest of the samples had raised total bilirubin and the highest was found in Javed a young male person aged 12 years. Similarly, in case of bilirubin direct all the blood samples showed increased level. The standard chromatograms of 10 different pesticides such as match, cypermethrin, deltamethrin, polytrin-C, diazinon, DDE, monocrotophos, DDT, malathion and permethrin were prepared on HPLC and their retention time (RT) was noted. Calculation was done for the quantity of pesticides residues from the peaks of chromatograms. Regarding pesticide residues, out of total 45 samples, only 20 persons were found positive for residues. The quantity of pesticide was determined by comparing xii the peak area of the standard pesticide with the sample peaks. After analysis, it was found that out of 20 samples deltamethrin and cypermethrin were found in noticeable amount in 6 samples. Also polytrin-C, malathion and permethrin were found in 2, 1 and 5 samples respectively. The pesticides such as match, diazinon, DDT and monocrotophoswere not detected in any sample.