اسم المؤلف:
تمارة احمد عبد الكريم العبيدي
اسم المشرف:
زينب منيب مالك الربيعي | غيد حسان عبد الهادي العبيدي
المستخلص:
تمثل الستيرويدات فئة هامة من العقاقير الطبيعية وكذلك الصناعية نظرا لقدرتها على اختراق الخلايا واداء بعض الوظائف البيولوجية الاساسية وبشكل رئيسي هي عوامل مضادة للفيروسات ومضادات للاورام. وتقسم الرسالة الحالية على ثلاثة فصول.يمثل الفصل الاول مقدمة عامة حو | Steroids represent an important class of natural as well as synthetic drugs because of their ability to penetrate cells and perform some of the most fundamental biological functions mainly as antitumor and antiviral agents. The present thesis is devided into three chapters.The first chapter represented a general introduction concerning the structures of some potent steroids, and the pathways of the synthetic adrenal steroids as well as their pharmacological importance in medicine, in general. This part is focused mainly also on the pregnenolone as an important potentially active steroid, including its structural modification at the hydroxyl and keto groups at C - 3 and C - 20 and their uses as antitumor agents. Mitsunobu, Suzuki reactions and aldol condensation as well as chalcon formation and their application at steroids have been described. The second chapter is concerned with the experimental work which included different synthetic methodology.The third chapter is the main part of the thesis, described the synthesis of new 3? - pregnenolone ester derivatives at C - 3 via Misunobu reaction of the carboxylic acid derivatives, such as : rhodamin B, indomethacin, naproxen, protocatecuic acid, vanillic acid and p - coumaric acid, which showed inversion in configuration at the ester group at C - 3. In addition, the synthesis of 17 - (4 - chloro - chalconyl)pregnen - 3? - ol has been described, which then treated with various substituted phenylboronic acids such as : 2,4 - difluoro - , 5 - carboxy - 3 - nitrop - ,4 - fluoro, 4 - thiomethyl - , 4 - hydroxy - , 2,4, - dimethoxy - , 4 - trimethylsilyl, 2 - triflouromethyl - , 3 - cyano, 4 - ethoxyphenyl boronic acids under Suzuki cross - coupling reaction conditions using Pd(PPh3)4 as a catalyst and Na2CO3 as a base to give the (E) - 3 - (substituted - [1,1’ - biphenyl] - 4 - yl) - 1 - (3? - hydroxy - pregnen - 17 - yl) - prop - 2 - en - 1 - one. Two compounds, 17 - acetyl - 5 - pregnen - 3? - yl) - 2 - (2,6 - bis(diethylamino) - 9H - xanthen - 9 - yl)benzoate, and 17 - ((E) - 3 - (4 - chlorophenyl)acryloyl) - 5 - pregnen - 3? - yl) - 2 - (2,6 - bis(diethylamino) - 9H - xanthen - 9 - yl)benzoate have been synthesized via coupling reaction using DCC as a coupling reagent to afford these ester with retention in configuration, aiming to study their fluorescence properties. Moreover, tritylation of the pregnenolone has been described to protect the alcohol at C - 3 during the structural modification of keto group at C - 20 under basic medium. The structures of all the synthesized compounds have been assigned from their 1H, 13C, and 2D NMR (HSQC, HMBC, COSY, NOESY) spectroscopy as well the as theoretical calculations of the HOMO and LUMO energies of the trans and cis isomers of the chalconyl pregnenolone aryl derivatives to compare them with the NMR data, which showed that trans isomer is energetically more favoured.Furthermore, the flourescence proroperties of the two rhodainyl pregnenolone esters have been studies which one show remarkable quantum yield (?F) in comparison to Rhodamin B itself.The anti - HIV activity of some arylated chalconyl pregnenolone derivatives have been studies and one of these analogues having diflouro substituents exhibited remarkable activity against HIV - 1 and 2. Therefore, the molecular modeling study of this analogue is performed and showed two hydrophobic interactions and one hydrogen bonding with the amino acids residues of the reverse transcriptase enzyme of HIV.
