An assessment study of known pyrazolopyrimidines: Chemical methodology and cellular activity
Introduction
Heterocyclic molecules with pyrazolopyrimidine skeleton as pharmacophore are established to be highly versatile and potent in unfolding pharmacologically active lead molecules. As depicted in (Fig. 1), there are several isomers of pyrazolopyrimidine known out of which 1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrazolo[4,3-d]pyrimidine, and pyrazolo[1,5-a]pyrimidine are important.
Most importantly, there is an analogy between the pyrazolopyrimidine moiety with the core structure of adenine moiety in DNA [1] (Fig. 2) which encourages researchers to frame up diverged synthetic methodologies and evaluate their biological potency.
The unique feature of this molecule is that all isoforms are pharmacologically active in nature and marketed as active pharmaceutical agents. For example as depicted in (Fig. 3) pyrazolo[1,5-a]pyridine and pyrazolo[1,5-b]pyridine are marketed as Zaleplon and Indiplon respectively under the pharmacological class of sedative-hypnotics. Moreover, pharmacological studies proved the importance of pyrazolo[1,5-a]pyridines as anti-trypanosomal [2], anxiolytic [3], KDR Kinase inhibitor [4], HMG-COA reductase inhibitor [5], and seretonin 5-HT6 receptor antagonist [6]. Pyrazolo[3,4-d]pyridine is marketed as allopurinol which decreases blood uric acid levels that subsequently prevents gout. It is also reported to encompass anticoccidial activity [7], anti-inflammatory activity [8], radioprotectant [9], anti-leishmanial [10] and tuberculostatic nature [11]. Similarly pyrazolo[4,3-d]pyridine has its applications as cytokinin antagonist [12], adenosine receptor antagonist [13], corticotrophin releasing factor receptor antagonist [14], phosphodiesterase 5 (PDE5) inhibitors [15], diagnostic agent [16], anti-viral and anti-fungal agent [17], anti-leishmanial [18]. Moreover it is marketed as Sildenafil which is used to treat male and female sexual dysfunction [19].
Phosphorylation of proteins is a key step in the regular cell functions [20], [20](a), [20](b). In this process, various protein kinases transfer gamma phosphate group from the ATP to the respective protein substrate hydroxyl group (tyrosine, threonine and serine hydroxyl group) promoting normal signaling pathways in cell metabolism [21]. Abnormal alterations such as mutations and excessive activation of protein kinases end up in deviation of signaling pathways finally leading to upregulation of tumor cells, neurological diseases, and diabetes etc. At this juncture, pyrazolopyrimidines compete with ATP in binding with bilobed Mg-ATP, a catalytic domain of protein kinase and inhibit the transfer of phosphate group to protein hydroxyl group. Such type of pyrazolopyrimidines are classified as type-I inhibitors which act by forming hydrogen bonds with kinase hinge and hydrophobic bonds with adenine ring [22]. Similarly, type-II inhibitors act by binding with catalytic sites of kinase and also with hydrophobic allosteric sites [23]. Type-III inhibitors mechanism of action is by exclusive binding with the allosteric site where as type-IV inhibitors bind to allosteric sites that are present at a distance of considerable Ǻ away from ATP binding region [24], [25]. Type-V inhibitors act by binding covalently with the catalytic site of specific protein kinase [26].
As part of our recent report on the diversity-oriented synthesis of bioactive heterocycles, [27], [27](a), [27](b), [28], [28](a), [28](b) we have highlighted mainly on key developments such as synthesis, pharmacology and challenges to the future design of pyrazolopyrimidines as drug molecule in this review. There are also several reports till date that exposed various chemical methodologies and pharmacological activities of pyrazolopyrimidines [29], [29](a), [29](b), [29](c), [29](d), [30], [30](a), [30](b), [30](c). The body of article is focused on chemical methodology and biological potency as kinase inhibitors, phosphodiesterase inhibitors, receptor agonists or antagonist. Detailed information on the common synthetic routes to pyrazolopyrimidines originating from pyrimidines, nitriles and pyrroles are reviewed which starts from Robins work in the early stages to the present day. Evaluation of pyrazolopyrimdines as pharmacophores has started in mid 1950's when Robins proposed a de novo synthetic methodology from pyrazoles. Infact most of the reported strategies from then are initiated either from pyrazoles or from pyrimidines. While considering the synthetic methodologies alone, amide and or amine functionalities are tethered to the pyrazole and pyrimidine rings before they are further cyclized to form an isomer of pyrazolopyrimidine. The strategies that are reported in this review provide detailed information of the protocols initiated from pyrazoles and pyrimidines. The discussion and forethought in this review will provide key solutions to resolve the current synthetic problems. Furthermore, we believe that by assembling all the synthetic techniques on one platform will also promote knowledge about current synthetic progress in the synthesis of pyrazolopyrimidine analogs and using that knowledge, it may be possible to develop new concepts and increase the diversity of synthetic routes to pyrazolopyrimidine analogs. Further, deep insight on the agonistic and inhibitory effect of pyrazolopyrimidine analogs on various targets are reported with IC50 values and specific structures strategically so that further functionalities could be added to improve the activity while further research is being done.
Section snippets
Pyrazolopyrimidines as kinases inhibitors
There are 538 different types of protein kinases making them third largest enzyme class and they are estimated for modifying one third of the human proteome [31]. Our objective is to discuss the work done covering from receptor tyrosine kinases to serine threonine kinases, and cytoplasmic tyrosine kinases till date.
Pyrazolopyrimidines as anti-cancer agents
Kassiou and his coworkers worked on the synthesis of boron-rich 1,2-closo and 7,8-nido pyrazolopyrimidines (Scheme 23) [63] for the efficient delivery of boron from binding sites of pyrazolopyrimidines into translocator protein [TSPO] of human glioma cells to treat cancer. Translocator protein is located in the outer mitochondrial membrane of cell [64] and is involved in steroidogenesis, regulation of cell growth, differentiation, and apoptosis. Upregulation of TSPO in variety of tumor cell
Pyrazolopyrimidines as phosphodiesterase inhibitors
In 1996, Dumaitre and his group worked on the synthesis of a series of 6-phenylpyrazolo[3, 4-d]pyrimidinones as specific inhibitors of cGMP Specific (type V) phosphodiesterase. PDEV inhibition is an interesting target as cGMP mediates vasorelaxation action of endothelium derived relaxing factor (NO), natriuretic and diuretic effect of ANF through activation of PKG (cGMP dependent protein kinase) due to which of its control, could be used in the treatment of hypertension and congestive heart
Pyrazolopyrimidines as receptor blockers
A3 adenosine receptor is found in many peripheral tissues, microglial cells, astrocytes and also overexpressed in different tumor cell types [102]. Depending on the degree of activation they may be involved in cell protection and also in cell death due to which both A3 receptor agonist and antagonist may be effective in cancer treatment.
In this context, Colotta and his group in 2013 worked on the synthesis of 2-arylpyrazolo [4, 3-d] pyrimidin-7-amino derivatives as A3 adenosine receptor
Future perspective and conclusion
Considering the importance of pyrazolopyrimidines biologically, many derivatives of its isomers were synthesized with different substitutions containing polar, non-polar groups to evaluate its pharmacological activity. Moreover, these molecules have diverse biological importance due to its widespread properties. Pyrazolo[3,4-d]pyrimidine, an isomer of pyrazolopyrimidine is analogous to adenine base pair of DNA, due to which it has emerged as an important pharmacophore to carry out research as
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors thank the Chancellor and Vice Chancellor of VIT Vellore for providing the opportunity to carry out this study. Further the authors R N Rao and KC wish to thank the management of this university for providing seed money as a research grant. Kaushik Chanda thanks CSIR-Govt. of India for funding through Grant no 01(2913)/17/EMR-II and ICMR-Govt. of India for funding through Grant no 45/03/2019-BIO/BMS.
References (110)
- et al.
Bioorg. Med. Chem. Lett.
(2002) - et al.
Bioorg. Med. Chem. Lett.
(2001) - et al.
Eur. J. Med. Chem.
(2010) - et al.
J. Saudi Chem. Soc.
(2015) - et al.
Bioorg. Med. Chem. Lett.
(2016) - et al.
Bioorg. Med. Chem. Lett.
(2011) - et al.
Nat. Rev. Can.
(2009) - et al.
Curr. Opin. Drug. Discov. Devel.
(2004) - et al.
Sci.
(2017)(b)R.N. Rao, B. MM, B. Maiti, R. Thakuria, K. Chanda, ACS Comb. Sci. 20 (2018)... - et al.
ACS Catal.
(2017)et al.Bioorg. Med. Chem.
(2018)et al.Eur. J. Med. Chem.
(2017)
J. Med. Chem.
J. Het. Chem.
J. Biomed. Biotechnol.
Bioorg. Med. Chem.
J. Med. Chem.
Bioorg. Med. Chem. Lett.
Chem. Lett.
Expert Opin Ther Targets.
Chem. Lett.
J. Med. Chem.
Chem. Lett.
Chem. Commun.
ChemMedChem
Eur. J. Med. Chem.
J. Natl. Cancer Inst.
Cancer
Eur. J. Med. Chem.
Cancer Res.
Prog. Histochem. Cytochem
Eur. J. Med. Chem.
Trends Pharmacol. Sci.
World Psychiatry.
Chem. Biodivers.
J. Med. Chem.
J. Med. Chem.
J. Med. Chem.
J. Med. Chem.
Bioorg. Chem.
J. Med. Chem.
J. Enzyme Inhib Med. Chem.
Plant Physiol.
J. Med. Chem.
J. Proteome Res.
Lab Chip
Org. Biomol. Chem.
Arch. Pharm. Chem. Life Sci.
ACS Chem. Biol.
Cited by (23)
Regioisomeric functionalization of azo-bridged nitropyrazoles: Pushing the density limit of catenated nitrogen systems
2024, Chemical Engineering JournalThe literature of heterocyclic chemistry, Part XX, 2020
2023, Advances in Heterocyclic ChemistryCitation Excerpt :The symbiotic relationship between drug discovery and organic chemistry.675 Enzyme inhibitors as anticancer agents.690–702 Various azoles as anticancer agents.709–712
A close look into the biological and synthetic aspects of fused pyrazole derivatives
2022, European Journal of Medicinal ChemistryCitation Excerpt :The fused systems behave distinguished features that make them fascinating and interesting targets for exploration and application [15,16]. Over the past few decades, broad-spectrum biological activities of fused pyrazole derivatives have been excavated [2,12,13,17–19]. Meanwhile, the synthetic routes have been disclosed [20].
An efficient approach to the synthesis of 7-thioxosubstituted [1,3]thiazolo[3,2-c]pyrimidines and evaluation of their antimicrobial and antioxidant activities
2022, Phosphorus, Sulfur and Silicon and the Related ElementsSix-membered ring systems: diazines and benzo derivatives
2021, Progress in Heterocyclic ChemistryCitation Excerpt :Two reviews discussed the significance of pyrazolopyrimidines in medicinal chemistry. While one focused on the pyrazolo[3,4-d]pyrimidine core, the other examined past synthetic protocols and reported biological activity of this class of compounds as a whole, including all of the isomers (20BC103801). Another review described the functionalization of pyrimidines, quinazolines, and quinoxalines via a dehydrogenation reaction employing alcohol-containing starting materials (20OBC2193).