Design, synthesis and molecular docking of new fused 1H-pyrroles, pyrrolo[3,2-d]pyrimidines and pyrrolo[3,2-e][1, 4]diazepine derivatives as potent EGFR/CDK2 inhibitors.
Ontology highlight
ABSTRACT:
SUBMITTER: Belal A
PROVIDER: S-EPMC9272933 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:In vitro evaluation of the halogenated pyrrolo[3,2-d]pyrimidines identified antiproliferative activities in compounds 1 and 2 against four different cancer cell lines. Upon screening of a series of pyrrolo[3,2-d]pyrimidines, the 2,4-Cl compound 1 was found to exhibit antiproliferative activity at low micromolar concentrations. Introduction of iodine at C7 resulted in significant enhancement of potency by reducing the IC50 into sub-micromolar levels, thereby suggesting the importance of a halogen at C7. This finding was further supported by an increased antiproliferative effect for 4 as compared to 3. Cell-cycle and apoptosis studies conducted on the two potent compounds 1 and 2 showed differences in their cytotoxic mechanisms in triple negative breast cancer MDA-MB-231 cells, wherein compound 1 induced cells to accumulate at the G2/M stage with little evidence of apoptotic death. In contrast, compound 2 robustly induced apoptosis with concomitant G2/M cell cycle arrest in this cell model.
| S-EPMC5661880 | biostudies-literature
Project description:A combined experimental and theoretical study of the two-photon absorption (2PA) properties of a series of quadrupolar molecules possessing a highly electron-rich heterocyclic core, pyrrolo[3,2-b]pyrrole, is presented. In agreement with quantum-chemical calculations, large 2PA cross-section values, ?2PA ?10(2) -10(3) ?GM (1?GM=10(50) ?cm(4) ?s?photon(-1) ), are observed at wavelengths of 650-700?nm, which correspond to the two-photon allowed but one-photon forbidden transitions. The calculations also predict that increased planarity of this molecule through removal of two N-substituents leads to further increase in the ?2PA values. Surprisingly, the most quadrupolar pyrrolo[3,2-b]pyrrole derivative, containing two 4-nitrophenyl substituents at positions 2 and 5, demonstrates a very strong solvatofluorochromic effect, with a fluorescence quantum yield as high as 0.96 in cyclohexane, whereas the fluorescence vanishes in DMSO.
| S-EPMC4713190 | biostudies-literature
Project description:We have developed an efficient and robust route to synthesize 4,5,7-trisubstituted pyrrolo[3,2-d]pyrimidines as potent kinase inhibitors. This solution-phase synthesis features a SNAr substitution reaction, cross-coupling reaction, one-pot reduction/reductive amination and N-alkylation reaction. These reactions occur rapidly with high yields and have broad substrate scopes. A variety of groups can be selectively introduced into the N5 and C7 positions of 4,5,7-trisubstituted pyrrolopyrimidines at a late stage of the synthesis, thereby providing a highly efficient approach to explore the structure-activity relationships of pyrrolopyrimidine derivatives. Four synthetic analogs have been profiled against a panel of 48 kinases and a new and selective FLT3 inhibitor 9 is identified.
| S-EPMC3724770 | biostudies-literature
Project description:A two-step route to strongly absorbing and efficiently orange to deep red fluorescent, doubly B/N-doped, ladder-type pyrrolo[3,2-b]pyrroles has been developed. We synthesize and study a series of derivatives of these four-coordinate boron-containing, nominally quadrupolar materials, which mostly exhibit one-photon absorption in the 500-600 nm range with the peak molar extinction coefficients reaching 150 000, and emission in the 520-670 nm range with the fluorescence quantum yields reaching 0.90. Within the family of these ultrastable dyes even small structural changes lead to significant variations of the photophysical properties, in some cases attributed to reversal of energy ordering of alternate-parity excited electronic states. Effective preservation of ground-state inversion symmetry was evidenced by very weak two-photon absorption (2PA) at excitation wavelengths corresponding to the lowest-energy, strongly one-photon allowed purely electronic transition. π-Expanded derivatives and those possessing electron-donating groups showed the most red-shifted absorption- and emission spectra, while displaying remarkably high peak 2PA cross-section (σ 2PA) values reaching ∼2400 GM at around 760 nm, corresponding to a two-photon allowed higher-energy excited state. At the same time, derivatives lacking π-expansion were found to have a relatively weak 2PA peak centered at ca. 800-900 nm with the maximum σ 2PA ∼50-250 GM. Our findings are augmented by theoretical calculations performed using TD-DFT method, which reproduce the main experimental trends, including the 2PA, in a nearly quantitative manner. Electrochemical studies revealed that the HOMO of the new dyes is located at ca. -5.35 eV making them relatively electron rich in spite of the presence of two B--N+ dative bonds. These dyes undergo a fully reversible first oxidation, located on the diphenylpyrrolo[3,2-b]pyrrole core, directly to the di(radical cation) stage.
| S-EPMC8672719 | biostudies-literature
Project description:Halogenated pyrrolo[3,2-d]pyrimidine analogues have shown antiproliferative activity in recent studies, with cell accumulation occurring in the G2 /M stage without apoptosis. However, the mechanism of action and pharmacokinetic (PK) profile of these compounds has yet to be determined. To investigate the PK profile of these compounds, a series of halogenated pyrrolo[3,2-d]pyrimidine compounds was synthesized and first tested for activity in various cancer cell lines followed by a mouse model. EC50 values ranged from 0.014 to 14.5??m, and maximum tolerated doses (MTD) in mice were between 5 and 10?mg?kg-1 . This indicates a wide variance in activity and toxicity that necessitates further study. To decrease toxicity, a second series of compounds was synthesized with N5-alkyl substitutions in an effort to slow the rate of metabolism, which was thought to be leading to the toxicity. The N-substituted compounds demonstrated comparable cell line activity (EC50 values between 0.83-7.3??m) with significantly decreased toxicity (MTD=40?mg?kg-1 ). Finally, the PK profile of the active N5-substituted compound shows a plasma half-life of 32.7?minutes, and rapid conversion into the parent unsubstituted analogue. Together, these data indicate that halogenated pyrrolo[3,2-d]pyrimidines present a promising lead into potent antiproliferative agents with tunable activity and toxicity, and rapid metabolism.
| S-EPMC5912934 | biostudies-literature
Project description:A thorough investigation has enabled the optimization of the synthesis of 1,4-dihydro-pyrrolo[3,2-b]pyrroles. Although salts of such metals as vanadium, niobium, cerium, and manganese were found to facilitate the formation of 1,4-dihydro-pyrrolo[3,2-b]pyrroles from amines, aldehydes, and diacetyl, we confirmed that iron salts are the most efficient catalysts. The conditions identified (first step: toluene/AcOH = 1:1, 1 h, 50 °C; second step: toluene/AcOH = 1:1, Fe(ClO4)3·H2O, 16 h, 50 °C) resulted in the formation of tetraarylpyrrolo[3,2-b]pyrroles in a 6-69% yield. For the first time, very electron-rich substituents (4-Me2NC6H4, 3-(OH)C6H4, pyrrol-2-yl) originating from aldehydes and sterically hindered substituents (2-ClC6H4, 2-BrC6H4, 2-CNC6H4, 2-(CO2Me)C6H4, 2-(TMS-C≡C)C6H4) present on anilines can be appended to the pyrrolo[3,2-b]pyrrole core. It is now also possible to prepare 1,4-dihydropyrrolo[3,2-b]pyrroles bearing an ordered arrangement of N-substituents and C-substituents ranging from coumarin, quinoline, phthalimide to truxene. These advances in scope enable independent regulations of many desired photophysical properties, including the Stokes shift value and emission color ranging from violet-blue through deep blue, green, yellow to red. Simultaneously, the optimized conditions have finally allowed the synthesis of these extremely promising heterocycles in amounts of more than 10 g per run without a concomitant decrease in yield or product contamination. Empowered with better functional group compatibility, novel derivatization strategies were developed.
| S-EPMC7656515 | biostudies-literature
Project description:Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions. Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity. For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used. As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of "open field" and "elevated plus maze" (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds 6n, 6b, and 7c. The studied compounds increase the latent time of first immobilization on the model of "forced swimming" (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound 6k bound tightly in the active site of GABAA receptor with a value of the scoring function that estimates free energy of binding (ΔG) at -7.95 kcal/mol, while compound 6n showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT1A receptor. Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect.
| S-EPMC8198642 | biostudies-literature
Project description:A new series of thiazolo[3,2-a]pyrimidine bromide salt derivatives 7a-d were synthesized from 3,4-dihydropyrimidinethione precursors. The target compounds were fully characterized by 1D- and 2D-NMR, high resolution ESI-MS/MS and single crystal X-ray diffraction analysis, which confirmed a regioselective 5H cyclization of the dihydropyrimidinethiones. All target compounds were evaluated in vitro as human acetylcholinesterase (hAChE) inhibitors via an Ellman-based colorimetric assay and showed good inhibition activities (better than 70% at 10 µM and IC50 values in the 1 µM range). Molecular docking simulations for all target products into hAChE were performed and confirmed strong binding to the enzyme. These results provide a promising and new starting point to improve acetylcholinesterase inhibitors and explore novel treatment options against Alzheimer's disease.
| S-EPMC6630738 | biostudies-literature
Project description:The discovery, synthesis and biological evaluations of a series of nine N5-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds with microtubule depolymerizing activity were identified. Some of these compounds also circumvent clinically relevant drug resistance mechanisms (expression of P-glycoprotein and βIII tubulin). Compounds 4, 5, and 8-13 were one to two-digit nanomolar (IC50) inhibitors of cancer cells in culture. Contrary to recent reports (Banerjee et al. J. Med. Chem.2018, 61, 1704-1718), the conformation of the most active compounds determined by 1H NMR and molecular modeling are similar to that reported previously and in keeping with recently reported X-ray crystal structures. Compound 11, freely water soluble as the HCl salt, afforded statistically significant inhibition of tumor growth in three xenograft models [MDA-MB-435, MDA-MB-231 and NCI/ADR-RES] compared with controls. Compound 11 did not display indications of animal toxicity and is currently slated for further preclinical development.
| S-EPMC6252143 | biostudies-literature
Project description:A straightforward route to 1,4-dihydropyrrolo[3,2-b]pyrroles comprised of two electron-withdrawing quinoline or tetrazolo[1,5-a]quinoline scaffolds has been developed. The versatile multicomponent reaction affording 1,4-dihydropyrrolo[3,2-b]pyrroles combined with intramolecular direct arylation enables assembly of these products in just three steps from anilines with overall yields exceeding 30%. The planarized, ladder-type heteroacenes possess up to 14 conjugated rings. These nominally quadrupolar materials exhibit efficient fluorescence with wavelengths spanning most of the visible spectrum from green-yellow for the dyes possessing biaryl bridges and orange-red for the fully fused systems. In many cases, the fluorescence quantum yields are large, the solvatofluorochromic effects are strong, and the fluorescence is maintained even in crystalline state. Analysis of the electronic structure of these molecular architectures using quantum chemical methods suggests that the character and position of the flanking heterocycle determine the shape of HOMO and LUMO and their extension to N-aryl substituents, influencing the values of molar absorption coefficient. An experimental study of the two-photon absorption (2PA) properties has revealed that it occurs in the 700-800 nm range with apparent deviation from the Laporte parity selection rule, which may be attributed to Hertzberg-Teller contribution to vibronically allowed 2PA transition.
| S-EPMC11002929 | biostudies-literature