Abstract
Small molecules drug conjugate mutual prodrug design (SMDC) composed of folate and lethal agent conjugate, rigidly bonded via hydrophilic bridge and self immolative disulfide bond ; represent new interesting approaches for cancer treatment , the component of SMDC intended for targeting folate receptor , along with greater conservation of component until reaching the target tumor tissue . The designing and synthesis of compound VI and VIII derived from 6-Mercaptopurine (6-MP) and Methotrexate ( MTX) conjugate altogether as mutual prodrugs were processed forward successfully by multistep reaction procedures , and by Thin Layer Chromatography (TLC) for preliminary detection of products and their intermediates, along with their purity. The structures of two final compounds and their intermediates were proclaimed by melting point measurement, infrared spectrometry and ¹HNMR analysis given results greatly correspond with theoretical proposed chemical structure of synthesized compounds. Furthermore, cytotoxic activity evaluation on cell line level had been done for two final compounds against human breast tumor cell (MCF-7) and human ovarian tumor cell (SKO-3) types of cancer cell line and the results were confirmed which show greater cytotoxic tumor activity of two final compounds, while compound VI possess optimal activity proportional with increased number of 6-MP molecules.
Highlights
Small molecules drug conjugate mutual prodrug design (SMDC) composed of folate and lethal agent conjugate, rigidly bonded via hydrophilic bridge and self immolative disulfide bond ; represent new interesting approaches for cancer treatment, the component of SMDC intended for targeting folate receptor, along with greater conservation of component until reaching the target tumor tissue
Most of chemicals for research need were supplied by (Hyperchem company/ China); these chemicals include 6-MPand MTX, dicyclo hexyl carbodiinmide (DCC), and 1-hydroxy benzotriazole (HOBT),while cysteine amino acid was supplied by, and 4-nitrophenylchloroformate from (Tci /china), purity determination and reaction progress following up realized by thin-layer chromatography (TLC), it was prepared by running diverse mobile phase on stationary phase prepared from coating silica gel F-254(type60) on thin film of aluminum(CHMLAB group/ Spain ).The final products and their intermediacy were revealed by attendant iodine vapor or simple irradiation with UV lamp(254nm), featuring melting points of final products and their intermediates were measured by capillary tube method, results accession on electric melting point instrument (Stuart value / England ), and they are uncorrected
MTX is protected on its two 1°amine group by carbamate formation by reaction of MTX in anhydrous DMF with 2equimolar of 4-nitrophenylchloroformate to produce compound V, same dry condition in same solvent required for compound VI synthesis by reaction of compounds V and IV with stirring at 25°C for 24 hrs
Summary
Small molecules drug conjugate mutual prodrug design (SMDC) composed of folate and lethal agent conjugate, rigidly bonded via hydrophilic bridge and self immolative disulfide bond ; represent new interesting approaches for cancer treatment , the component of SMDC intended for targeting folate receptor , along with greater conservation of component until reaching the target tumor tissue. The designing and synthesis of compound VI and VIII derived from 6-Mercaptopurine (6-MP) and Methotrexate ( MTX) conjugate altogether as mutual prodrugs were processed forward successfully by multistep reaction procedures , and by Thin Layer Chromatography (TLC) for preliminary detection of products and their intermediates, along with their purity. وتحليل الرنين النووي المغناطيسي, التحليل الطيفي للاشعة تحت الحمراء, المركبين النهائيين مع مركباتهم الوسطية تم اثباته بقياس درجة الانصهار
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