Avanafil: A comprehensive drug profile.

Avanafil is an oral medication used to treat erectile dysfunction (ED). As a phosphodiesterase type 5 (PDE5) inhibitor, it functions by inhibiting the PDE5 enzyme, which ultimately results in increased levels of cyclic guanosine monophosphate (cGMP) and improved blood flow to the penis. Approved by the FDA in 2012, avanafil is recognised for its rapid onset of action, short half-life, and favourable side-effects profile. While it has been explored for other potential therapeutic applications, its current approved use is limited to ED and should be used as prescribed by a medical professional. This chapter provides a comprehensive review of avanafil, encompassing its nomenclature, physicochemical properties, methods of preparation, and identification. Various techniques for analysing avanafil, such as electrochemical analysis, spectrophotometric, spectrofluorimetric, and chromatographic techniques, are discussed. The pharmacology of avanafil, including its pharmacokinetics and pharmacodynamics, is also examined.

Ponatinib: A comprehensive drug profile.

Ponatinib is a prescription medication used to treat a rare form of blood cancer called Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML) that is resistant to other treatments. It belongs to a class of drugs called tyrosine kinase inhibitors, which work by blocking abnormal proteins that promote the growth of cancer cells. In this chapter, the synthesis methods and physicochemical properties of ponatinib were reviewed, besides the characterization of the ponatinib structure using different techniques such as elemental analysis, IR, UV, (1H and 13C) NMR, MS, and XRD. Furthermore, the compendial method for analysis of ponatinib was not found, while the literature review of a non-compendial method for analysis of ponatinib, such as spectroscopic, chromatographic, and immunoassay methods, was covered. Moreover, pharmacology and biochemistry were surveyed in the pharmacokinetic and pharmacodynamic studies.

Design, synthesis, and carbonic anhydrase inhibition activities of Schiff bases incorporating benzenesulfonamide scaffold: Molecular docking application.

In this study, The inhibitory actions of human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII are being examined using recently synthesized substituted hydroxyl Schiff derivatives based on the quinazoline scaffold 4-22. Quinazolines 2, 3, 4, 5, 7, 10, 15, and 18 reduce the activity of hCA I isoform effectively to a Ki of 87.6-692.3 nM, which is nearly equivalent to or more potent than that of the standard drug AAZ (Ki, 250.0 nM). Similarly, quinazolines 2, 3, and 5 and quinazoline 14 effectively decrease the inhibitory activity of the hCA II isoform to a KI of 16.9-29.7 nM, comparable to that of AAZ (Ki, 12.0 nM). The hCA IX isoform activity is substantially diminished by quinazolines 2-12 and 14-21 (Ki, 8.9-88.3 nM against AAZ (Ki, 25.0 nM). Further, the activity of the hCA XII isoform is markedly inhibited by the quinazolines 3, 5, 7, 14, and 16 (Ki, 5.4-19.5 nM). Significant selectivity levels are demonstrated for inhibiting tumour-associated isoforms hCA IX over hCAI, for sulfonamide derivatives 6-15 (SI; 10.68-186.29), and 17-22 (SI; 12.52-57.65) compared to AAZ (SI; 10.0). Sulfonamide derivatives 4-22 (SI; 0.50-20.77) demonstrated a unique selectivity in the concurrent inhibition of hCA IX over hCA II compared to AAZ (SI; 0.48). Simultaneously, benzenesulfonamide derivative 14 revealed excellent selectivity for inhibiting hCA XII over hCA I (SI; 60.35), whereas compounds 5-8, 12-14, 16, and 18-22 demonstrated remarkable selectivity for hCA XII inhibitory activity over hCA II (SI; 2.09-7.27) compared to AAZ (SI; 43.86 and 2.10, respectively). Molecular docking studies additionally support 8 to hCA IX and XII binding, thus indicating its potential as a lead compound for inhibitor development.

Synthesis of novel spirochromane incorporating Schiff's bases, potential antiproliferative activity, and dual EGFR/HER2 inhibition: Cell cycle analysis and in silico study.

Spirochromanes incorporating Schiff's bases and semicarbazones 4a-e and 5a-j were synthesizedand analyzed for their potential antiproliferative activity using four human cancer cell lines (MCF-7, HCT-116, PC3, and A549). Compounds 5a, 5b and 5g possessed the highest antiproliferative activity among the tested compounds,with an IC50 range of 1.154-9.09 µM. Compound 5j selectively inhibited the PC3 cell proliferation (IC50 = 5.47 µM). Spirochromanes 5a, 5b and 5g exhibited high inhibitory activity against EGFR (IC50 = 0.116, 0.132, and 0.077 µM, respectively) and HER2 (IC50 = 0.055, 0.210 and 0.085 µM, respectively) compared with the references, erlotinib (IC50 = 0.090 and 0.038 µM, respectively) and gefitinib (IC50 = 0.052 and 0.072 µM, respectively). Cell cycle analysis and apoptosis results showed that compounds 5a, 5b and 5g arrested growth inthe S phase, and the programmed cell death induced by these compounds was an apoptotic mechanism rather than a necrotic pathway. Molecular docking studies of spirochromanes 5a, 5b and 5g to EGFR and HER2 binding sites were performed to explore the orientation mode and interaction.

Synthesis and In Vitro Anticancer Activity of Novel 4-Aryl-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridines Arrest Cell Cycle and Induce Cell Apoptosis by Inhibiting CDK2 and/or CDK9.

Two series of pyrazolo[3,4-b]pyridine derivatives, 9a-h and 14a-h, are synthesized and evaluated for their anti-cancer potency towards Hela, MCF7, and HCT-116 cancer cell lines. Compound 9a showed the highest anticancer activity with IC50 = 2.59 µM against Hela when compared with doxorubicin (IC50 = 2.35 µM). Compound 14g revealed cytotoxicity IC50 = 4.66 and 1.98 µM towards MCF7 and HCT-116 compared to doxorubicin with IC50 = 4.57 and 2.11 µM, respectively. Compound 9a exhibited cell cycle arrest at the S phase for Hela, whereas 14g revealed an arresting cell cycle for MCF7 at G2/M phase and an arresting cell cycle at S phase in HCT-116. In addition, 9a induced a significant level of early and late apoptosis in Hela when compared with the control cells, whereas 14g induced an apoptosis in MCF7 and HCT-116, respectively. Compounds 9a (IC50 = 26.44 ± 3.23 µM) and 14g (IC50 = 21.81 ± 2.96 µM) showed good safety profiles on normal cell line WI-38. Compounds 9a and 14g showed good inhibition activity towards CDK2, with IC50 = 1.630 ± 0.009 and 0.460 ± 0.024 µM, respectively, when compared with ribociclib (IC50 = 0.068 ± 0.004). Furthermore, 9a and 14g showed inhibitory activity towards CDK9 with IC50 = 0.262 ± 0.013 and 0.801 ± 0.041 µM, respectively, related to IC50 of ribociclib = 0.050 ± 0.003. Docking study for 9a and 14g exhibited good fitting in the CDK2 and CDK9 active sites.

Optimization, Kinetics, and Isotherm Studies of Methyl Thioninium Chloride Removal from Simulated Solutions Using Chitosan Derivatives.

Methylene blue (MB) dye or methyl thioninium chloride is one of the hazardous cationic dyes that are discharged into the textile effluent causing a highly negative environmental impact. The present work targets the investigation of the adsorption performance of some chitosan-modified products toward the MB dye from simulated solutions. The claimed chitosan derivatives were prepared, characterized, and applied for the removal of lead and copper cations from an aqueous medium in a previous work. These include: N,O-carboxymethyl chitosan (N,O-CM/Cs), chitosan grafted with glutaraldehyde (Cs/GA), chitosan cross-linked with GA/epichlorohydrin (Cs/GA/ECH), and chitosan cross-linked with glutaraldehyde/methylene bis(acrylamide) (Cs/GA/MBA). The modified chitosan derivatives in this study displayed outstanding mechanical qualities, exceptional reusability, and a significant amount of adsorption capacity. The ability of prepared Cs derivatives to eradicate MB was as follows: N,O-CM/Cs (95.1 mg/g) < Cs/GA (120.1 mg/g) < Cs/GA/ECH (220.1 mg/g) < Cs/GA/MBA (270.0 mg/g). The swelling performance of the prepared sorbents was verified under different experimental conditions, and the data revealed that the maximum swelling was attained at pH = 9, temperature 55 °C, and after 24 h. The produced Cs derivatives showed exceptional reusability by maintaining higher adsorption effectiveness throughout five cycles. The MB dye was adsorbed onto the modified derivatives according to pseudo-second-order kinetics and the Langmuir model. Moreover, the adsorption process was monitored via atomic force microscopy to verify the differences between the dye-free and dye-loaded adsorbents.

LC-MS/MS method for the quantitation of decitabine and venetoclax in rat plasma after SPE: Application to pharmacokinetic study.

This study developed a novel, sensitive and selective LC-MS/MS method for the concurrent determination of DCB and VTX in rat plasma using encorafenib as internal standard (IS). To identify DCB, VTX, and IS, the positive multiple reaction monitoring (MRM) mode was used. Chromatographic separation was carried out using a reversed-phase Agilent Eclipse plus C18 column (100 mm × 2.1 mm, 3.5 µm) and an isocratic mobile phase made up of water with 0.1% formic acid and acetonitrile (50:50, v/v, pH 3.2) at a flow rate of 0.30 mL/min for 3.0 min. Prior to analysis, the DCB and VTX with the IS were extracted from plasma using the solid-phase extraction (SPE) method. High recovery rates for DCB, VTX and IS were achieved using the C18 cartridge without interference from plasma endogenous. The developed method was validated as per the FDA guidelines over a linear concentration range in rat plasma from 5-3000 and 5-1000 ng/mL for DCB and VTX, respectively with r2 ≥ 0.998. For both drugs, the lower limits of detection (LLOD) were 2.0 ng/mL. After the HLOQ sample was injected, less than 20% of the LLOQ of DCB, VTX, and less than 5% of the IS carry-over in the blank sample was attained. The overall recoveries of DCB and VTX from rat plasma were in the range of 90.68-97.56%, and the mean RSD of accuracy and precision results was ≤6.84%. For the first time, the newly developed approach was effectively used in a pharmacokinetic study on the simultaneous oral administration of DCB and VTX in rats that received 15.0 mg/kg of DCB and 100.0 mg/kg of VTX.

Chitosan-Based Architectures as an Effective Approach for the Removal of Some Toxic Species from Aqueous Media.

Modified uncrosslinked and crosslinked chitosan derivatives were investigated as green sorbents for the removal of copper (Cu2+) and lead (Pb2+) cations from simulated solutions. In this regard, N, O carboxymethyl chitosan (N, O CMC), chitosan beads (Cs-g-GA), chitosan crosslinked with glutaraldehyde/methylene bisacrylamide (Cs/GA/MBA), and chitosan crosslinked with GA/epichlorohydrin (Cs/GA/ECH) were prepared and characterized by Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, and scanning electron microscopy analyses. Atomic force microscopy investigation was carried out to compare the surface topography of the prepared samples before and after the metal uptake. The kinetics of the removal process were investigated by pseudo-first-order and -second-order models. Moreover, the adsorption isotherms were carefully studied by applying Langmuir and Freundlich models. The data reveal that upon adsorption of copper(II) metal ions, all chitosan-modified products followed the Langmuir isotherm except for Cs/GA/ECH which followed the Freundlich isotherms, and the highest adsorption capacity (q e) was obtained for Cs/GA/MBA due to the formation of stable chelate structures between the metal cation and the functional groups present on the modified chitosan product. The order of metal uptake at the optimum pH value is as follows: Cs/GA/MBA (Cu: 95.7 mg/g, Pb: 99.15 mg/g), Cs/GA/ECH (Cu: 80.4 mg/g, Pb: 93.14 mg/g), Cs-g-GA (Cu: 77 mg/g, Pb: 88.4 mg/g), and N, O CMCh (Cu: 30.2 mg/g, Pb: 44.8 mg/g). The AFM data confirmed the metal uptake process by comparing the roughness and height measurements of the free sorbents and the metal-loaded sorbents.

Trends in monoliths: Packings, stationary phases and nanoparticles.

Monoliths media are gaining interest as excellent substitutes to conventional particle-packed columns. Monolithic columns show higher permeability and lower flow resistance than conventional liquid chromatography columns, providing high-throughput performance, resolution and separation in short run times. Monolithic columns with longer length, smaller inner diameter and specific selectivity to peptides or enantiomers have been played important role in hyphenated system. Monolithic stationary phases possess great efficiency, resolution, selectivity and sensitivity in the separation of complex biological samples, such as the complex mixtures of peptides for proteome analysis. The development of monolithic stationary phases has opened the new avenue in chromatographic separation science and is in turn playing much more important roles in the wide application area. Monolithic stationary phases have been widely used in fast and high efficiency one- and multi-dimensional separation systems, miniaturized devices, and hyphenated system coupled with mass spectrometers. The developing technology for preparation of monolithic stationary phases is revolutionizing the column technology for the separation of complex biological samples. These techniques using porous monoliths offer several advantages, including miniaturization and on-line coupling with analytical instruments. Additionally, monoliths are ideal support media for imprinting template-specific sites, resulting in the so-called molecularly-imprinted monoliths, with ultra-high selectivity. In this review, the origin of the concept, the differences between their characteristics and those of traditional packings, their advantages and drawbacks, theory of separations, the methods for the monoliths preparation of different forms, nanoparticle monoliths and metal-organic framework are discussed. Two application areas of monolithic metal-organic framework and nanoparticle monoliths are provided. The review article discusses the results reported in a total of 218 references. Other older references were included to illustrate the historical development of monoliths, both in preparation and types, as well as separation mechanism.

Carbonic Anhydrase Inhibition Activities of Schiff's Bases Based on Quinazoline-Linked Benzenesulfonamide.

Human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII were investigated for their inhibitory activity with a series of new Schiff's bases based on quinazoline scaffold 4-27. The hCA I isoform was efficiently inhibited by Schiff's bases 4-6, 10-19, 22-27 and had an inhibition constant (Ki) value of 52.8-991.7 nM compared with AAZ (Ki, 250 nM). Amongst the quinazoline derivatives, the compounds 2, 3, 4, 10, 11, 16, 18, 24, 26, and 27 were proven to be effective hCA II inhibitors, with Ki values of 10.8-52.6 nM, measuring up to AAZ (Ki, 12 nM). Compounds 2-27 revealed compelling hCA IX inhibitory interest with Ki values of 10.5-99.6 nM, rivaling AAZ (Ki, 25.0 nM). Quinazoline derivatives 3, 10, 11, 13, 15-19, and 24 possessed potent hCA XII inhibitory activities with KI values of 5.4-25.5 nM vs. 5.7 nM of AAZ. Schiff's bases 7, 8, 9, and 21 represented attractive antitumor hCA IX carbonic anhydrase inhibitors (CAIs) with KI rates (22.0, 34.8, 49.2, and 45.3 nM, respectively). Compounds 5, 7, 8, 9, 14, 18, 19, and 21 showed hCA I inhibitors on hCA IX with a selectivity index of 22.46-107, while derivatives 12, 14, and 18 showed selective hCA I inhibitors on hCA XII with a selectivity profile of 45.04-58.58, in contrast to AAZ (SI, 10.0 and 43.86). Compounds 2, 5, 7-14, 19-23, and 25 showed a selectivity profile for hCA II inhibitors over hCA IX with a selectivity index of 2.02-19.67, whereas derivatives 5, 7, 8, 13, 14, 15, 17, 20, 21, and 22 showed selective hCA II inhibitors on hCA XII with a selectivity profile of 4.84-26.60 balanced to AAZ (SI, 0.48 and 2.10).

Synthesis, antitumor, and apoptosis-inducing activities of novel 5-arylidenethiazolidine-2,4-dione derivatives: Histone deacetylases inhibitory activity and molecular docking study.

The antitumor activity of the newly synthesized 5-arylidenethiazolidine-2,4-dione derivatives 18a-f and 19a-f was investigated, compared to doxorubicin (IC50 = 4.17-8.87 µM) and SAHA (IC50 = 2.70-7.11 µM). Among the tested molecules, compounds 18b, 18c, 18f, 19d, and 19e displayed the highest antitumor activity against cancer cell lines (IC50 = 3.16-28.94 µM). Further, compounds 18b, 18c, 18f, and 19d were tested as Histone deacetylases (HDACs) inhibitors compared with Entinostat (IC50 = 0.093-0.75 µM). Compounds 18b, 18c, 18f, and 19d inhibited HDAC1, HDAC2, HDAC8, and HDAC6 enzymes with IC50 values ranging from 0.144 to 1.741 µM. In addition, compound 18b caused apoptosis via a mitochondrial-mediated pathway and led to cell cycle arrest at the G1 phase. It also increased caspases-3 and caspases-7 by 5.2-3.9 and 9.1-3.7 folds, respectively. The molecular docking analysis of compounds 18b and 18c revealed that they could bind to the active sites of HDAC1, HDAC2, HDAC8, and HDAC6 like co-crystallized inhibitors.

Design, synthesis, antitumor, and VEGFR-2 inhibition activities of novel 4-anilino-2-vinyl-quinazolines: Molecular modeling studies.

The antitumor activity of newly synthesized 4-anilino-2-vinylquinazolines 8a-r was measured comparable to sorafenib as a standard drug. The 2-vinylquinazolines 8a-r were evaluated for their in vitro antitumor activity. The most active antitumor agents were subjected to in vitro VEGFR-2 inhibition and apoptotic inducing assay. Compounds 8 h, 8 l, and 8r showed potential antitumor activities with IC50 values of 4.92-14.37 µM relative to the reference drug, sorafenib (IC50 values of 5.47-9.18 µM). Compound 8 h possessed potential VEGFR-2 inhibitory activity (IC50 = 60.27 nM) compared to standard drug sorafenib (IC50 = 55.43 nM), whereas compound 8 l showed moderate inhibitory activity (IC50 = 93.50 nM). The most active compound, 8 h, exhibited total apoptosis with 36.24% on MCF-7 cells, more than the apoptotic effect provoked by sorafenib (32.46%) and the cell cycle arrested at a G1/S phase. Compound 8 h, a potent VEGFR-2 inhibitor, was docked into the VEGFR-2 binding pocket, where this compound showed binding interaction similar to co-crystallized inhibitor sorafenib.

Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 Inhibitors.

Cyclin-dependent kinase 9 (CDK9) plays a critical role in transcriptional elongation, through which short-lived antiapoptotic proteins are overexpressed and make cancer cells resistant to apoptosis. Therefore, CDK9 inhibition depletes antiapoptotic proteins, which in turn leads to the reinstatement of apoptosis in cancer cells. Twenty-seven compounds were synthesized, and their CDK9 inhibitory and cytotoxic activities were evaluated. Compounds 7, 9, and 25 were the most potent CDK9 inhibitors, with IC50 values of 0.115, 0.131, and 0.142 µM, respectively. The binding modes of these molecules were studied via molecular docking, which shows that they occupy the adenosine triphosphate binding site of CDK9. Of these three molecules, compound 25 shows good drug-like properties, as it does not violate Lipinski's rule of five. In addition, this molecule shows promising ligand and lipophilic efficiency values and is an ideal candidate for further optimization.

Synthesis, potential antitumor activity, cell cycle analysis, and multitarget mechanisms of novel hydrazones incorporating a 4-methylsulfonylbenzene scaffold: a molecular docking study.

Hydrazone is a bioactive pharmacophore that can be used to design antitumor agents. We synthesised a series of hydrazones (compounds 4-24) incorporating a 4-methylsulfonylbenzene scaffold and analysed their potential antitumor activity. Compounds 6, 9, 16, and 20 had the most antitumor activity with a positive cytotoxic effect (PCE) of 52/59, 27/59, 59/59, and 59/59, respectively, while compounds 5, 10, 14, 15, 18, and 19 had a moderate antitumor activity with a PCE of 11/59-14/59. Compound 20 was the most active and had a mean 50% cell growth inhibition (GI50) of 0.26 µM. Compounds 9 and 20 showed the highest inhibitory activity against COX-2, with a half-maximal inhibitory concentration (IC50) of 2.97 and 6.94 µM, respectively. Compounds 16 and 20 significantly inhibited EGFR (IC50 = 0.2 and 0.19 µM, respectively) and HER2 (IC50 = 0.13 and 0.07 µM, respectively). Molecular docking studies of derivatives 9, 16, and 20 into the binding sites of COX-2, EGFR, and HER2 were carried out to explore the interaction mode and the structural requirements for antitumor activity.

Design, synthesis, and analysis of antiproliferative and apoptosis-inducing activities of nitrile derivatives containing a benzofuran scaffold: EGFR inhibition assay and molecular modelling study.

New cyanobenzofurans derivatives 2-12 were synthesised, and their antiproliferative activity was examined compared to doxorubicin and Afatinib (IC50 = 4.17-8.87 and 5.5-11.2 µM, respectively). Compounds 2 and 8 exhibited broad-spectrum activity against HePG2 (IC50 = 16.08-23.67 µM), HCT-116 (IC50 = 8.81-13.85 µM), and MCF-7 (IC50 = 8.36-17.28 µM) cell lines. Compounds 2, 3, 8, 10, and 11 were tested as EGFR-TK inhibitors to demonstrate their possible anti-tumour mechanism compared to gefitinib (IC50 = 0.90 µM). Compounds 2, 3, 10, and 11 displayed significant EGFR TK inhibitory activity with IC50 of 0.81-1.12 µM. Compounds 3 and 11 induced apoptosis at the Pre-G phase and cell cycle arrest at the G2/M phase. They also increased the level of caspase-3 by 5.7- and 7.3-fold, respectively. The molecular docking analysis of compounds 2, 3, 10, and 11 indicated that they could bind to the active site of EGFR TK.

Betaxolol: A comprehensive profile.

Betaxolol is a relatively cardioselective ß-adrenoceptor blocking drug, with no partial agonist (intrinsic sympathomimetic) activity and weak membrane-stabilizing (local anesthetic) activity. Betaxolol selectively and competitively binds to and blocks beta-1 (ß1) adrenergic receptors in the heart, thereby decreasing cardiac contractility and rate. This leads to a reduction in cardiac output and lowers blood pressure. When applied topically in the eye, this agent reduces aqueous humor secretion and lowers the intraocular pressure (IOP). In addition, betaxolol prevents the release of renin, a hormone secreted by the kidneys that causes constriction of blood vessels. Betaxolol (S)-(-)-enantiomer shows higher pharmacological activity. This chapter provides a complete review of nomenclature, physiochemical properties, methods of preparation, identification techniques and various qualitative and quantitative analytical techniques as well as pharmacology of betaxolol. In addition, the chapter also includes review of several methods for enantiomeric separation betaxolol using chromatographic techniques.

Co-Inhibition of P-gp and Hsp90 by an Isatin-Derived Compound Contributes to the Increase of the Chemosensitivity of MCF7/ADR-Resistant Cells to Doxorubicin.

Breast cancer is a complex and multi-drug resistant (MDR) disease, which could result in the failure of many chemotherapeutic clinical agents. Discovering effective molecules from natural products or by derivatization from known compounds is the interest of many research studies. The first objective of the present study is to investigate the cytotoxic combinatorial, chemosensitizing, and apoptotic effects of an isatin derived compound (5,5-diphenylimidazolidine-2,4-dione conjugated with 5-substituted isatin, named HAA2021 in the present study) against breast cancer cells (MCF7) and breast cancer cells resistant to doxorubicin (MCF7/ADR) when combined with doxorubicin. The second objective is to investigate the binding mode of HAA2021 withP-glycoprotein (P-gp) and heat shock protein 90 (Hsp90), and to determine whether their co-inhibition by HAA2021 contribute to the increase of the chemosensitization of MCF7/ADR cells to doxorubicin. The combination of HAA2021, at non-toxic doses, with doxorubicin synergistically inhibited the proliferation while inducing significant apoptosis in MCF7 cells. Moreover, HAA2021 increased the chemosensitization of MCF7/ADR cells to doxorubicin, resulting in increased cytotoxicity/selectivity and apoptosis-inducing efficiency compared with the effect of doxorubicin or HAA2021 alone against MCF7/ADR cells. Molecular modeling showed that two molecules of HAA2021 bind to P-gp at the same time, causing P-gp inhibitory effect of the MDR efflux pump, and accumulation of Rhodamine-123 (Rho123) in MCF7/ADR cells. Furthermore, HAA2021 stably interacted with Hsp90α more efficiently compared with 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), which was confirmed with the surface plasmon resonance (SPR) and molecular modeling studies. Additionally, HAA2021 showed multi-target effects via the inhibition of Hsp90 and nuclear factor kappa B (NF-𝜅B) proteins in MCF7 and MCF7/ADR cells. Results of real time-PCR also confirmed the synergistic co-inhibition of P-gp/Hsp90α genes in MCF7/ADR cells. Further pharmacokinetic and in vivo studies are warranted for HAA2021 to confirm its anticancer capabilities.

Antitumor activity, multitarget mechanisms, and molecular docking studies of quinazoline derivatives based on a benzenesulfonamide scaffold: Cell cycle analysis.

The in vitro cytotoxicity of some substituted quinazolinones, 1-15, was evaluated using NCI (10 µM) in a full NCI 59-cell line panel assay. Relative to the reference drug, imatinib (PCE = 20/59), compounds 3, 4, 7, 9, and 10 exhibited remarkable antitumor activity against the tested cell lines, with positive cytotoxic effects (PCE) of 29/59, 18/59, 17/59, 44/59, and 24/59 respectively. Enzymatic inhibitory assay conducted on 3, 4, 9, and 10 as the most potent antitumor agents against EGFR, HER2 and CDK9 kinases, and COX-2 enzyme. Compound 3 possessed good COX-2 inhibitory activity (IC50 = 0.775 µM) compared to the reference drug, celecoxib (IC50 = 0.153 µM). Compounds 4 and 9 were closely potent to the reference compounds against EGFR and (HER2) tyrosine kinases, with IC50 values of 90.17 (and 131.39 for HER2) for 4 and 145.35 (and 129.07 for HER2) nM for 9; the reference drugs in this case, namely, gefitinib and erlotinib, exhibited IC50 values of 55.58 (90) and 110 (79.28) nM against the EGFR and (HER2) tyrosine kinases, respectively. Compound 4 was approximately similar potent against CDK9 kinase (IC50 = 67.04 nM) like the reference compound, dinaciclib (IC50 = 53.12 nM). Compound 9 induced cytotoxicity in the MCF-7 cell line (GI % at 10.0 µM = 47%) through pre-G1 apoptosis, thereby inhibiting cell growth at the G2/M phase. Molecular docking models of 3 and 4 with COX-2, EGFR, and CDK9 were conducted to determine their binding mode within the putative binding pockets.

Design, synthesis, and antitumor activity of novel compounds based on 1,2,4-triazolophthalazine scaffold: Apoptosis-inductive and PCAF-inhibitory effects.

The antitumor activity of newly synthesised triazolophthalazines (L-45 analogues) 10-32 was evaluated in human hepatocellular carcinoma (HePG-2), breast cancer (MCF-7), prostate cancer (PC3), and colorectal carcinoma (HCT-116) cells. Compounds 17, 18, 25, and 32 showed potent antitumor activity (IC50, 2.83-13.97 µM), similar to doxorubicin (IC50, 4.17-8.87 µM) and afatinib (IC50, 5.4-11.4 µM). HePG2 was inhibited by compounds 10, 17, 18, 25, 26, and 32 (IC50, 3.06-10.5 µM), similar to doxorubicin (IC50, 4.50 µM) and afatinib (IC50, 5.4 µM). HCT-116 and MCF-7 were susceptible to compounds 10, 17, 18, 25, and 32 (IC50, 2.83-10.36 and 5.69-11.36 µM, respectively), similar to doxorubicin and afatinib (IC50 = 5.23 and 4.17, and 11.4 and 7.1 µM, respectively). Compounds 17, 25, and 32 exerted potent activities against PC3 (IC50, 7.56-12.28 µM) compared with doxorubicin (IC50, 8.87 µM) and afatinib (IC50 7.7 µM). Compounds 17 and 32 were the strongest PCAF inhibitors (IC50, 5.31 and 10.30 µM, respectively) and compounds 18 and 25 exhibited modest IC50 values (17.09 and 32.96 µM, respectively) compared with bromosporine (IC50, 5.00 µM). Compound 17 was cytotoxic to HePG2 cells (IC50, 3.06 µM), inducing apoptosis in the pre-G phase and arresting the cell cycle in the G2/M phase. Molecular docking for the most active PCAF inhibitors (17 and 32) was performed.

Synergistic Anti Leukemia Effect of a Novel Hsp90 and a Pan Cyclin Dependent Kinase Inhibitors.

Acute myeloid leukemia (AML) is among the top four malignancies in Saudi nationals, and it is the top leukemia subtype worldwide. Resistance to available AML drugs requires the identification of new targets and agents. Hsp90 is one of the emerging important targets in AML, which has a central role in the regulation of apoptosis and cell proliferation through client proteins including the growth factor receptors and cyclin dependent kinases. The objective of the first part of this study is to investigate the putative Hsp90 inhibition activity of three novel previously synthesized quinazolines, which showed HL60 cytotoxicity and VEGFR2 and EGFR kinases inhibition activities. Using surface plasmon resonance, compound 1 (HAA2020) showed better Hsp90 inhibition compared to 17-AAG, and a docking study revealed that it fits nicely into the ATPase site. The objective of the second part is to maximize the anti-leukemic activity of HAA2020, which was combined with each of the eleven standard inhibitors. The best resulting synergistic effect in HL60 cells was with the pan cyclin-dependent kinases (CDK) inhibitor dinaciclib, using an MTT assay. Furthermore, the inhibiting effect of the Hsp90α gene by the combination of HAA2020 and dinaciclib was associated with increased caspase-7 and TNF-α, leading to apoptosis in HL60 cells. In addition, the combination upregulated p27 simultaneously with the inhibition of cyclinD3 and CDK2, leading to abolished HL60 proliferation and survival. The actions of HAA2020 propagated the apoptotic and cell cycle control properties of dinaciclib, showing the importance of co-targeting Hsp90 and CDK, which could lead to the better management of leukemia.