Design, synthesis and pharmacological evaluation of novel fused pyrimidine analogues as anticancer agents.
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Date
2018
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Abstract
Cancer is a multifaceted disease considered as the most serious health burden all over the world. Due
to existing of limited anticancer drugs and detrimental side effects, the anticancer research has been
challenging. An investigation on identifying novel potential drugs is highly required to treat this serious
abnormal cell growth. Advanced potential anticancer drug entrants are crucially required to combat the
drawbacks linked with current drugs or line of therapies. Extensive investigations are being carried out
on synthetic manipulations of heterocyclic aromatic compounds (purines) for developing efficient and
potent anticancer drugs. Besides, these manipulations also offer effective leads for further optimization.
Therefore, this project is an effort in detecting a novel and potent anticancer leads based on bioisostere
of purines called pyrazolopyrimidines.
In this research project we have performed an comprehensive literature survey of structural isomers of
pyrazolopyrimidines (pyrazolo[1,5-a]pyrimidine and pyrazolo[4,3-d]pyrimidine) for their synthetic
approaches and biological activities with special emphasis on structure-activity relationship (SAR)
studies. These SAR studies prompted us to implement the observed studies on one of the structural
isomer of pyrazolopyrimidine called pyrazolo[3,4-d]pyrimidine. And further, we have synthesized
some novel series of pyrazolo[3,4-d]pyrimidine derivatives with various substituents at C-4 and C-6
positions of the scaffold. A total 71 compounds comprising of phenethyl and pentane hybrids (7-43,
Chapter 4), benzoyl hybrids (5a-5h, 6a-6d and 7a-7c, Chapter 5) and lastly phenylcarbamoyl acetamide
hybrids (9a-9s, Chapter 6) have been synthesized by molecular hybridization approach as outlined in
schemes of respective chapters. The completion of reaction and the purity of novel synthesized
compounds were confirmed by chromatographic analysis. All the newly synthesized compounds
displayed acceptable analysis for their anticipated structures, which were established based on
physicochemical and spectral data (IR, 1
H NMR, 13C NMR and HRMS).
All synthesized compounds were primarily evaluated for their in vitro anticancer activities at
Laboratory of Growth Regulators, Centre of the Region Hana for Biotechnological and Agricultural
Research, Palacky University & Institute of Experimental Botany ASCR, Slechtitelu 27, 78371
Olomouc, Czech Republic.
From the systematic analysis of anticancer activity, results obtained following key observations were
made.
i. Structural isomers of fused pyrimidines have been looked upon for molecular changes in
emerging drug like candidates. Pyrazolopyrimidine is a bioisostere of purines has acquired
considerable importance due to its diverse, facile and general synthetic methodologies with
great medicinal importance. Several analogs of this scaffold have emerged as a promising
leads in the design of some novel pharmacologically active compounds with enhanced
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metabolic, pharmacokinetic and pharmacological profiles, representing that there is plenty
scope for considering pyrazolopyrimidine as a structural framework for evolving effective
leads.
ii. Chapter 4: From the 37 novel phenethyl and alkyl pentane pyrazolo[3,4-d]pyrimidine
derivatives synthesized and evaluated for CDK2/Cyclin E, Abl kinase inhibitory activity
and anti-proliferative activity against K-562 (chronic myelogeneous leukemia) and MCF7 (breast adenocarcinoma) cell lines. From the tested results, compounds 11 (CDK: IC50 =
5.1 µM; Abl: ˃12.5 µM), 8 (CDK: IC50 = 7.8 µM; Abl: ˃25 µM) and 36 (CDK: IC50 = 8.8
µM; Abl: >25 µM) exhibited significant inhibitory activity. Further from this series, most
of the synthesized compounds indicated prominent anti-proliferative effects with IC50 value
ranging from 19.2 µM to 27.4 µM. Incorporation of monosubstituted phenyl groups at C-4
of the pyrazolo[3,4-d]pyrimidine nucleus had favored for most prominent anticancer
activity.
iii. Chapter 5: Among the 15 novel benzoyl hybrids synthesized and evaluated, compounds 5a
and 6c displayed (CDK2: IC50 = 8.8 µM, 6.8 µM) commendable inhibitory activity and
notable anti-proliferative activity ranging from 18.9 µM to 89.3 µM). Presence of
heteroatom containing bicyclic moieties at C-4 of the nucleus enhanced both inhibitory and
anti-proliferative activity.
iv. Chapter 6: Of the 19 novel phenylcarbamoyl acetamide hybrids synthesized and tested,
compounds 9a, 9c, 9g, 9m and 9p showed moderate enzymatic inhibitory activity with an
IC50 value ˃12.5 µM against both CDK2 and Abl kinases while, remaining compounds of
this series could not generate IC50 values due to solubility limit (IC50 = ˃25 µM to ˃100
µM).
Description
Doctoral Degree. University of KwaZulu-Natal, Durban.