Novel pyrazolo[4,3-d]pyrimidine microtubule targeting agents (MTAs): Synthesis, structure–activity relationship, in vitro and in vivo evaluation as antitumor agents

Islam, Farhana; Quadery, Tasdique M.; Bai, Ruoli; Luckett-Chastain, Lerin R.; Hamel, Ernest; Ihnat, Michael A.; Gangjee, Aleem

doi:10.1016/j.bmcl.2021.127923

Cited by 12 publications

(13 citation statements)

References 40 publications

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“…Overall, active LDL particles encapsulated pyrimidine heterocyclic anticancer agents targeted both cell lines with similar potency at 10 µM> 5 µM> 1 µM as shown in Figure 7 . Mimicking pyrimidine's native amino acid structures benefits cancer treatment and causes cell growth reduction (Yao et al, 2017 ; Islam et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, heterocyclic fused pyrimidines agents were synthesized as tubulin polymerization inhibitors to target the colchicine domain, the agents inhibited tumor growth in the A375 melanoma xenograft model, increased apoptosis, and disruption of tumor vasculature (Banerjee et al, 2018 ). Furthermore, new series of pyrimidine derivatives synthesized as inhibitors of tubulin polymerization and colchicine domain, the data revealed excellent potency in MCF7 cell death in the nano-molar levels (≤10 nM) (Islam et al, 2021 ). Generally, pyrimidines derivatives are used as anticancer agets (Nasser et al, 2016 ; El Sayed et al, 2020 ) targeting different cellular proteins such as tubulin (Sana et al, 2021 ), HSP90 (Davies et al, 2012 ), and vascular endothelial growth factor (VEGF) receptor (Aziz et al, 2016 ; Dawood et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Cancer targeted drug delivery using active low-density lipoprotein nanoparticles encapsulated pyrimidines heterocyclic anticancer agents as microtubule inhibitors

2022

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Recently, nanomedicine had the potential to increase the delivery of active compounds to specific cell sites. Nano-LDL particles are recognized as an excellent active nano-platform for cancer-targeted delivery. Loading of therapeutic agents into nano-LDL particles achieved by surface loading, core loading, and apolipoprotein-B100 interaction. Therefore, loading nano-LDL particles’ core with pyrimidine heterocyclic anticancer agents will increase cancer cytotoxic activity targeting tubulin protein. First, by mimicking the native LDL particle's metabolic pathway, and second the agent’s chemical functional groups like the native amino acids cytosine and thymine structures will not be recognized as a foreign entity from the cell’s immune system. Nano-LDL particles will internalize through LDL-receptors endocytosis and transport the anticancer agent into the middle of the cancer cell, reducing its side effects on other healthy cells. Generally, the data revealed that pyrimidine heterocyclic anticancer agents’ size is at the nano level. Agents’ morphological examination showed nanofibers, thin sheets, clusters, and rod-like structures. LDL particles’ size became bigger after loading with pyrimidine heterocyclic anticancer agents and ranged between 121.6 and 1045 nm. Then, particles were tested for their cytotoxicity against breast (MDA468) and prostate (DU145) cancer cell lines as surrogate models with dose-response study 10, 5, 1 µM. The IC 50 values of the agents against DU145 and MDA468 possessed cell growth inhibition even at the 1 µM concentration ranges of 3.88 ± 1.05 µM and 3.39 ± 0.97 µM, respectively. In sum, nano-LDL particles proved their efficiency as active drug delivery vehicles to target tubulin in cancer cells.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cancer targeted drug delivery using active low-density lipoprotein nanoparticles encapsulated pyrimidines heterocyclic anticancer agents as microtubule inhibitors

2022

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“…Cyclization of 16 with chloro-formamidine hydrochloride, formamide and acetonitrile afforded 17 , 18 and 19 , respectively, using reported methods [ 25 , 45 , 46 ]. Chlorination [ 47 ] of 17 – 19 with POCl 3 and pyridine in toluene afforded 20 – 22 in 68–75% yield.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

et al. 2022

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A series of eleven 4-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines were designed and synthesized and their biological activities were evaluated. Synthesis involved the Gewald reaction to synthesize ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate ring, and SNAr reactions. Compound 4 was 1.6- and ~7-fold more potent than the lead compound 1 in cell proliferation and microtubule depolymerization assays, respectively. Compounds 4, 5 and 7 showed the most potent antiproliferative effects (IC50 values < 40 nM), while compounds 6, 8, 10, 12 and 13 had lower antiproliferative potencies (IC50 values of 53–125 nM). Additionally, compounds 4–8, 10 and 12–13 circumvented Pgp and βIII-tubulin mediated drug resistance, mechanisms that diminish the clinical efficacy of paclitaxel (PTX). In the NCI-60 cell line panel, compound 4 exhibited an average GI50 of ~10 nM in the 40 most sensitive cell lines. Compound 4 demonstrated statistically significant antitumor effects in a murine MDA-MB-435 xenograft model.

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“…In this regard, chemists make many and various attempts to discover novel pyrimidine derivatives via different synthetic strategies and utilize various important catalysts [ 13 , 14 , 15 ]. Fused pyrimidines were designed and evaluated as antitumors [ 16 ], antioxidants [ 17 ], and anticancer [ 18 ]. In addition, imidazopyrimidines exhibited highly biological activities where they act as anti-inflammatory [ 19 ], antimicrobial [ 20 ], and cytotoxic agents [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Molecular Docking, and Evaluation Antioxidant and Antimicrobial Activities for Novel 3-Phenylimidazolidin-4-One and 2-Aminothiazol-4-One Derivatives

et al. 2022

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On our way to discovering and developing compounds that have an antioxidant impact compared to ascorbic acid and other biological activities, we designed, synthesized, and evaluated a new series of heterocyclic moieties drugs (1–11) as antioxidants and antimicrobial agents. As starting moieties, these new candidates were derived from two promising heterocyclic compounds, imidazoldin-4-one and thiazol-4-one. Firstly, diphenylimidazol 1 was obtained because of the cyclo condensation one-pot ternary reaction of urea, aniline, and chloroacetic acid under thermal conditions. Out of this starting compound, we could design and create new vital rings such as purine and triazine as in compounds 5 and 6, respectively. Secondly, the start thiazole derivative 7 was obtained from the intermolecular cyclization of thiourea, chloroacetic acid, p-nitobezaldehyde in the presence of sodium acetate. We synthesized various derivatives from this second starting compound 7 by being subjected to different reagents such as aniline, phenylenediamine, phenylhydrazine, and barbituric acid to yield 8, 9, 10, and 11, respectively. Using ascorbic acid as the standard compound, the pharmacological testing for antioxidant activity assessment of the produced derivatives was evaluated against ABTS (2,20-azinobis (3-ethylbenzothiazoline-6-sulfonic acid). Candidate 6 exhibited the best activity as an antioxidant agent compared to ascorbic acid as a reference compound. Moreover, all compounds were evaluated as antimicrobial agents against a series of bacteria and fungi. Among all synthesized compounds, compound 6 achieved high efficiency against two types of fungi and four kinds of bacteria, as Clotrimazole and Ampicillin were used as the reference agents, respectively. All chemical structures of the novel synthesized candidates were unequivocally elucidated and confirmed utilizing spectroscopical and elemental investigations.

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Novel pyrazolo[4,3-d]pyrimidine microtubule targeting agents (MTAs): Synthesis, structure–activity relationship, in vitro and in vivo evaluation as antitumor agents

Cited by 12 publications

References 40 publications

Cancer targeted drug delivery using active low-density lipoprotein nanoparticles encapsulated pyrimidines heterocyclic anticancer agents as microtubule inhibitors

Cancer targeted drug delivery using active low-density lipoprotein nanoparticles encapsulated pyrimidines heterocyclic anticancer agents as microtubule inhibitors

Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

Design, Synthesis, Molecular Docking, and Evaluation Antioxidant and Antimicrobial Activities for Novel 3-Phenylimidazolidin-4-One and 2-Aminothiazol-4-One Derivatives

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