Design by Synthesis and Biological Screening of Antitumor Anthracycline Aza-analogues; A Quantative Structure Activity Relationship (QSAR) Analysis Study

الموضوعات

طب

الملخص

A training set of eleven known anthracyclines were picked from literature andsome of their physiochemical parameters were calculated using semiempirical quantum mechanical methodsand correlated with their reportedexperimental biological activity data. These are the ID50values in vitroof themodel anthracyclines against L1210 leukemia and two human colon tumourcell lines (Colon 4 and HT 29). Extensive statistical correlations between thephysiochemical parameters (total energy,heat of formation, dipole momentand molecular refractivity) and ID50values were executed to yield about fourhundred tables of paired data. The tableswhich give the highest r-values werechosen for further treatment. Thus two tables for each cell line were obtained,one represents one hour in vitroincubation and the other represents continuousincubation versus one of the calculated physiochemical parameters. Totalenergy parameters as calculated by AM1 and PM3 (used as such ortransformed into their reciprocals) were found to give the highest linearcorrelation coefficients. Upon establishing a correlation between thephysiochemical parameters and biological response (ID50), mathematicalformulas were derived and used to calculate the anticipated biologicalresponses of a designed set of hypothetical aza-analogue of the training set.This designed set contains three groups of aza-analogues of daunorubicin (15compounds), aclarubicin (5 compounds) and rhodomycin (27 compounds).Physiochemical parameters of these aza-analogues were likewise calculatedand used in aforementioned mathematical model to compute their biologicalactivity data. Upon scrutiny, the calculated ID50values show very explicit andorderly trends which correlate well with calculated log P values of thedesigned set. The present QSAR model was found to be sensitive to theexpected active cites in the designed set that are similar to those of the trainingset. Our set of designed anthracycline aza-analogues shows two uniformactivity profile; one for both incubationsagainst Colon 4 and the other forboth incubation against HT 29 cell lines while L1210 cell line partitionedbetween the two activity profile with one hour incubation mode lining up withColon 4 and continuous incubation mode with HT 29. It also reveals thatactivity is directly proportional to lipophilicity for aza-daunorubicin and azarhodomycin groups while aza-aclarubicins exhibits the reverse behaviour. Themost important outcome of this in silicomodel is the indication that the 2-Naza-analogues are generally more active than 1-N aza-analogue, a well-knownbehavior for aza-anthracenediones and aza-anthrapyrazoles hitherto unknownfor anthracyclines.

روابط وملفات

التعريف والنوع

رقم الوثيقة

ef6d3105-1fdb-4bb2-aa05-63016bd777e2

رقم العقد

0

نوع الوسائط

Crawler

نوع المحتوى

الرسائل العلمية

صيغة المصدر

رسائل دكتوراة

نوع الملف

pdf text

أسماء الملفات

1639173_1.pdf

بيانات النشر

ألقاب المؤلفين

[{"name_ar":"Abdalla Awad Abdalla","title_ar":"اشراف","title_en":"Supervision"},{"name_ar":"Mohammed Osman Moahammed Ahmed El-Fakki","title_ar":"اعداد","title_en":"Preparation"}]

اللغة

English

المصدر والدورية

اسم المصدر

Design by Synthesis and Biological Screening of Antitumor Anthracycline Aza-analogues; A Quantative Structure Activity Relationship (QSAR) Analysis Study

المحتوى والصفحات

عدد الصفحات

0

إشراف وإعداد

الإشراف

Abdalla Awad Abdalla

الإعداد

Mohammed Osman Moahammed Ahmed El-Fakki

الاقتباسات الببليوغرافية