Antiproliferative Research Articles

Benzimidazole-Based Derivatives as Apoptotic Antiproliferative Agents: Design, Synthesis, Docking, and Mechanistic Studies.

A new class of benzimidazole-based derivatives (4a-j, 5, and 6) with potential dual inhibition of EGFR and BRAFV600E has been developed. The newly synthesized compounds were submitted for testing for antiproliferative activity against the NCI-60 cell line. All newly synthesized compounds 4a-j, 5, and 6 were selected for testing against a panel of sixty cancer cell lines at a single concentration of 10 µM. Some compounds tested demonstrated remarkable antiproliferative activity against the cell lines tested. Compounds 4c, 4e, and 4g were chosen for five-dose testing against 60 human tumor cell lines. Compound 4c demonstrated strong selectivity against the leukemia subpanel, with a selectivity ratio of 5.96 at the GI50 level. The most effective in vitro anti-cancer assay derivatives (4c, 4d, 4e, 4g, and 4h) were tested for EGFR and BRAFV600E inhibition as potential targets for antiproliferative action. The results revealed that compounds 4c and 4e have significant antiproliferative activity as dual EGFR/BRAFV600E inhibitors. Compounds 4c and 4e induced apoptosis by increasing caspase-3, caspase-8, and Bax levels while decreasing the anti-apoptotic Bcl2 protein. Moreover, molecular docking studies confirmed the potential of compounds 4c and 4e to act as dual EGFR/BRAFV600E inhibitors.

Study of the Potential of Rice Bran as an Anticancer: A Systematic Literature Review

The bioactive compounds in rice bran have various health benefits, including anticancer potential. Cancer is a disease characterized by uncontrolled cell growth. Cancer cells can originate from any cell in the body and can spread to other parts of the body. Cancer is one of the highest causes of death in the world. The literature search process was carried out on various databases (PubMed, Web of Sciences, EMBASE, Cochrane Libraries, and Google Scholar) regarding analysis of the anti-cancer potential of rice bran. This study follows the preferred reporting items for systematic reviews and meta-analysis (PRISMA) recommendations. Rice bran contains various bioactive compounds, including antioxidants, anti-inflammatory, anti-proliferative, and apoptosis-inducing agents. These compounds can work together to inhibit the growth of cancer cells and prevent their spread.

Highly hydrophilic methacrylamide-based copolymers as precursors for polymeric nanomedicines containing anthracyclines

The crucial limitation of most low molecular weight cytostatic drugs, including anthracyclines, is their nonspecific biodistribution causing severe adverse effects during cancer treatment. Recently, nanomedicines such as polymer-based systems have been developed as advanced drug delivery systems. Herein, we report the design, synthesis, and characterization of highly water-soluble polymer-carriers based on N‑(1,3‑dihydroxyprop-2-yl)methacrylamide (DHPMA). Polymers differing in molecular weight, hydrodynamic size, and dispersity were synthesized via free or controlled radical polymerization and conjugated to an anthracycline drug pirarubicin (THP) via a pH-sensitive hydrazone bond achieving up to 21 wt% of THP. The DHPMA copolymers were extensively compared to the well-known drug delivery vectors, N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymers. Importantly, DHPMA-based conjugates showed excellent hydrophilicity exceeding that of HPMA-based copolymers and did not aggregate even after loading with THP reaching 21 wt%. The DHPMA-based polymer nanomedicines exhibited excellent cytotoxicity, body biodistribution, tumor accumulation, and antitumor efficacy, significantly reducing the side effects and toxicity comparable to HPMA-based systems, thus demonstrating their applicability and suitability as efficient drug carriers.

The microtubule cytoskeleton: A validated target for the development of 2-Aryl-1H-benzo[d]imidazole derivatives as potential anticancer agents

In this study, a series of 2-Aryl-1H-benzo[d]imidazole derivatives were developed to target intra- and extracellular microtubule networks. Compounds O-7 and O-10 showed impressive anti-proliferative activity across various tested cell lines, demonstrating selectivity indexes of 151.7 and 61.9, respectively. O-7 achieved an IC50 value of 0.236 ± 0.096 μM, while O-10 showed an IC50 value of 0.622 ± 0.13 μM against A549 cell lines. The induction of early-stage apoptosis in a dose-dependent manner further underscored the potential of O-7 and O-10 as effective anti-proliferative agents. O-7 and O-10 exhibited substantial inhibition of wound closure, with wound closure percentages decreasing from 23% at 0 μM to 0.43% and 2.62% at 20 μM, respectively. Colony formation reduction rates were impressive, with O-7 at 74.2% and O-10 at 81.2%. These results indicate that the O-7 and O-10 can impede cancer cell migration and have a high potential to curtail colony formation. The mode of action investigations for O-7 and O-10 revealed that O-7 could inhibit in vitro tubulin polymerization and disrupt the intracellular microtubule cytoskeleton. This disruption led to cell cycle arrest in the G2/M phase, indicating that O-7 exerts its anticancer activity through microtubule destabilization. However, O-10 shows a different mode of action than O-7 and requires further investigation. Overall, our study showcases the potential of the synthesized benzimidazole derivatives as novel and selective anticancer agents, motivating further exploration of their pharmacological properties and therapeutic applications.

Design and synthesis of new 1,2,4-oxadiazole/quinazoline-4-one hybrids with antiproliferative activity as multitargeted inhibitors.

The combination of BRAF and tyrosine kinase (TK) inhibitors has been demonstrated to be highly effective in inhibiting tumor development and is an approach for overcoming resistance in clinical trials. Accordingly, a novel series of 1,2,4-oxadiazole/quinazoline-4-one hybrids was developed as antiproliferative multitargeted inhibitors. The structures of the newly synthesized compounds 9a-o were validated using IR, NMR, MS, and elemental techniques. 9a-o were tested as antiproliferative agents. The results showed that the majority of the tested compounds showed significant antiproliferative action with 9b, 9c, 9h, 9k, and 9l being the most potent. Compounds 9b, 9c, 9h, 9k, and 9l were tested as EGFR and BRAFV600E inhibitors. These in vitro tests revealed that compounds 9b, 9c, and 9h are strong antiproliferative agents that may act as dual EGFR/BRAFV600E inhibitors. 9b, 9c, and 9h were further investigated for their inhibitory effect on mutant EGFR (EGFRT790M), and the results showed that the tested compounds had considerable inhibitory action. Cell cycle study and apoptosis detection demonstrated that compound 9b exhibits cell cycle arrest at the G2/M transition. Molecular docking simulations reveal the binding mechanism of the most active antiproliferative agents.

Efficacy of mTOR Inhibitors and Intravenous Immunoglobulin for Treatment of Polyoma BK Nephropathy in Kidney Transplant Recipients: A Biopsy-Proven Study.

We investigated the efficacy of a predetermined protocol that consisted of immunosuppressive drug reduction/withdrawal and intravenous immunoglobulin administration for the treatment of polyoma BK virus nephropathy. Patients with biopsy-proven polyoma BK virus nephropathy received a treatment regimen based on discontinuation of both calcineurin inhibitors and antiproliferative agents and switching to mTOR inhibitors accompanied by intravenous immunoglobulin administration. Our study included 508 patients, with polyoma BK viremia detected in 80 patients. The mean age was 45.3 ± 9.5 years (range, 18-71 y), 64% were male, and mean follow-up was 37 ± 21 months (6-94 mo). All 16 patients who developed polyoma BK virus nephropathy and 9 patients who had highgrade polyoma BK viremia without nephropathy received intravenous immunoglobulin treatment. Compared with patients with viremia, patients with polyoma BK virus nephropathy had significantly higher rates of graft loss due to rejection (18.8% vs 1.6%; P = .024) and all-cause graft loss (31.2% vs 6.3%; P = .014). Histopathologically, viral inclusion bodies disappeared and SV40 became negative after treatment in all 13 patients who underwent protocol biopsies. Unfortunately, histopathologically complete recovery without chronic tubular and interstitial tissue damage was achieved in only 4 patients after treatment. In addition, 3 patients lost their grafts due to acute antibody-mediated or mixed-type rejection (18.8%). In patients with polyoma BK virus nephropathy, clearance of viremia and SV40 should not be the sole outcomes to obtain. Aggressive reductions in maintenance immunosuppression and switching to double-drug therapy combined with high-dose intravenous immunoglobulin leads to high rates of graft loss/rejection and sequalae of chronic histological changes.

Potential of asiaticoside encapsulated alginate chitosan nanoparticles in the management of antiproliferative activity in C6 glioma cells

BackgroundAsiaticoside is a pentacyclic triterpenoid saponin constituent of the medicinal herb Centella asiatica, known for its neuroprotective, anticancer and other biological effects. The present study aims to develop and characterise asiaticoside encapsulated alginate chitosan nanoparticles (ACNPs) and evaluate their antiproliferative potential on C6 glioma cells. MethodsACNPs were prepared by the ionic gelation polyelectrolyte complexation technique and characterised by dynamic light scattering, scanning electron microscopy and transmission electron microscopy. Cytotoxicity and antiproliferative effect of ACNPs were studied on C6 glioma cells using MTT and EdU-assays. Apoptosis/necrosis in C6 glioma cells was determined by annexin V and acridine orange/ethidium bromide (AO/EtBr) assays. Intracellular ROS generation in C6 glioma cells exposed with ACNP was determined by DCFDA assay using flow cytometry. Cell cycle analysis in C6 glioma cells treated with ACNP was performed by flow cytometry. ResultsSynthesised ACNPs showed spherical shape with 200 nm particle size, good thermal stability, and an acceptable polydispersity index. ASI from synthesized ACNPs demonstrated 90% encapsulation efficiency (EE) and 10% drug release within 24 h. Upon ACNP treatment mBA cells exhibited good cell viability and intact cell morphology. However, C6 cells displayed dose-dependent cytotoxicity when treated with ACNP. Annexin V and acridine orange/ethidium bromide (AO/EtBr) assays revealed late apoptosis and necrosis (p < 0.05) in C6 glioma cells treated with ACNP. Likewise, ACNPs significantly augmented reactive oxygen species generation (p < 0.05) in C6 glioma cells. ACNP treatment also resulted in cell cycle arrest at the G1 phase with chromatin condensation in C6 glioma cells. ConclusionsThese findings suggest that ACNPs act as an antiproliferative agent against C6 glioma cells via an increased intracellular ROS pathway that promotes apoptosis/necrosis. This study throws light on more in-depth mechanistic aspects of managing brain disorders using C. asiatica and its phytoconstituents.

Synthesis of a new series of 4-pyrazolylquinolinones with apoptotic antiproliferative effects as dual EGFR/BRAFV600E inhibitors.

The current study focuses on developing a single molecule that acts as an antiproliferative agent with dual or multi-targeted action, reducing drug resistance and adverse effects. A new series of 4-pyrazolylquinolin-2-ones (5a-j) with apoptotic antiproliferative effects as dual EGFR/BRAFV600E inhibitors were designed and synthesized. Compounds 5a-j were investigated for their cell viability effect against a normal cell line (MCF-10A). Results showed that none of the compounds were cytotoxic, and all 5a-j demonstrated more than 90% cell viability at 50 μM concentration. Using erlotinib as a reference, the MTT assay investigated the antiproliferative impact of targets 5a-j against four human cancer cell lines. Compounds 5e, 5f, 5h, 5i, and 5j were the most potent antiproliferative agents with GI50 values of 42, 26, 29, 34, and 37 nM, making compounds 5f and 5h more potent than erlotinib (GI50 = 33 nM). Moreover, compounds 5e, 5f, 5h, 5i, and 5j were further investigated as dual EGFR/BRAFV600E inhibitors, and results revealed that compounds 5f, 5h, and 5i are potent antiproliferative agents that act as dual EGFR/BRAFV600E inhibitors. Cell cycle analysis and apoptosis detection revealed that compound 5h displaying cell cycle arrest at the G1 transition could induce apoptosis with a high necrosis percentage. Docking studies revealed that compound 5f exhibited a strong affinity for EGFR and BRAFV600E, with high docking scores of -8.55 kcal mol-1 and -8.22 kcal mol-1, respectively. Furthermore, the ADME analysis of compounds 5a-j highlighted the diversity in their pharmacokinetic properties, emphasizing the importance of experimental validation.

Design and synthesis of novel 2-(2-(4-bromophenyl)quinolin-4-yl)-1,3,4-oxadiazole derivatives as anticancer and antimicrobial candidates: in vitro and in silico studies.

Cancer is the second leading cause of death globally, surpassed only by heart disease. Moreover, bacterial infections remain a significant global health burden, contributing substantially to morbidity and mortality, especially among hospitalized patients. EGFR has emerged as a prime therapeutic target due to its pivotal role in driving uncontrolled cell growth and survival across numerous cancer types. In addition, DNA gyrase represents a promising target for the development of novel antimicrobial agents. Therefore, we aimed to design and synthesize new multi-target quinoline hybrids (7-17e) capable of acting as anti-proliferative and antimicrobial agents by inhibiting EGFR and microbial DNA gyrase, respectively. The inhibitory potential of the synthesized compounds was determined using in vitro and in silico approaches. The antiproliferative activity of the synthesized quinoline-oxadiazole derivatives 7-17e was assessed against two cancer cell lines, namely, hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7). The assessed compounds 7-17e showed considerable cytotoxic activity activities against HepG2 and MCF-7 with IC50 values of 0.137-0.332 and 0.164-0.583 μg mL-1, respectively, in comparison to erlotinib as the positive control, which showed an IC50 value of 0.308 and 0.512 μg mL-1, respectively. Moreover, an EGFR tyrosine kinase inhibition assay was conducted on the most prominent candidates. The results showed good IC50 values of 0.14 and 0.18 μM for compounds 8c and 12d, respectively, compared to lapatinib (IC50 value of 0.12 μM). Furthermore, the minimum antimicrobial inhibitory concentration was evaluated for the most prominent candidates with S. aureus, E. coli, and C. albicans. Compounds 17b, 17d and 17e displayed the most potent inhibitory activity, exhibiting 4-, 16- and 8-fold more activity, respectively, than the reference neomycin. Hence, we can conclude that the afforded compounds can be used as lead dual anticancer and antimicrobial candidates for future optimization.

Alkoxy-functionalised dihydropyrimido[4,5-b]quinolinones enabling anti-proliferative and anti-invasive agents.

In this communication, we explored the synthesis of novel alkoxy-functionalised dihydropyrimido[4,5-b]quinolinones using a microwave-assisted multicomponent reaction. All the synthesized molecules were screened for anti-proliferative and anti-invasive activity against glioblastoma cells. 5c shows the most potent anti-proliferative activity with a half maximal effective concentration of less than 3 μM against primary patient-derived glioblastoma cells. 5c effectively inhibited invasion and tumor growth of 3D primary glioma cultures in a basement membrane matrix. This suggests that the novel compounds could inhibit both the proliferation and invasive spread of glioma and they were selected for further study.

Citric Acid Treatment of Refractory Chronic Postmastectomy Raw Area During Chemotherapy: A Novel Approach

Background. Wounds at sutured sites are a major postoperative complication. Uncontrolled comorbidities and certain drugs (immunosuppressants and antiproliferative chemotherapeutic agents) hamper the process of wound healing. Sutured wounds need prolonged duration of dressings and management as well as repeated hospital visits. In addition, appropriate reconstructive procedures may be needed to cover the wound. All these factors ultimately add to the cost of care. Case Report. A simple, yet effective option for the management of a refractory chronic postoperative raw area in a surgical case of breast carcinoma is reported. Acceptable wound healing was eventually achieved without disturbing the patient’s chemotherapy cycles, and a major reconstructive procedure was avoided. Conclusion. Citric acid treatment can be a cost-effective, safe, efficient, and novel option to promote faster granulation and epithelialization and may avoid the need for major reconstructive surgery.

Study on erythropoiesis-, leukopoiesis- and thrombocytopoiesis – stimulating activity of compounds BIV-241, BIV-242, BIV-243

The significance of the study is due to the problem of the increase in patients with secondary forms of leukopoiesis-depressive diseases. The development of leukopoiesis-stimulating drugs is necessary. These drugs are used in the treatment of cancer patients to prevent the development of febrile neutropenia, to stimulate the immune system in the postoperative period, to restore immune reactivity in environmentally caused secondary immunodeficiency syndrome. The rate of increase in patients with the secondary form of leukopoiesis-depressive syndrome is due to the increased use of cytostatic drugs. Preclinical work was carried out to study new synthetic compounds BIV-241 (dimethyl ((4-methoxyphenyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phosphonate), BIV-242 (dimethyl ((3-methoxyphenyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phosphonate), BIV-243 (dimethyl ((2-fluorophenyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phosphonate) for leukopoiesis-stimulating activity. The studies were conducted on a cyclophosphamide-induced model of pancytopenia on outbred white rats. Compounds BIV-241 and BIV-242 did not show the desired activity. Compound BIV-243 is of interest for further development, as it had moderate leukopoiesis-, erythrocytopoiesis- and thrombocytopoiesis-stimulating activity.

Ингаляционное применение ультранизких доз алкилирующих препаратов у пациента с рецидивирующей криптогенной организующейся пневмонией

The treatment tactics for a morphologically confirmed diagnosis of cryptogenic organizing pneumonia (COP) typically involves systemic glucocorticoids (SGCs) as the primary therapeutic agents. These drugs commonly lead to the regression of clinical, radiological, and pathomorphological changes. However, a substantial number of patients experience disease relapse upon dose reduction or discontinuation of SGCs, necessitating an increased dose, prolonged courses, or alternative therapeutic approaches. Alternative treatments may include the adjunct or standalone administration of cytostatic drugs such as azathioprine, cyclophosphamide, or mycophenolate mofetil. In these scenarios, there is no standardized approach for dosing either SGCs or cytostatics, even though treatment duration may extend over several months. It is important to consider that medications from both classes are associated with significant side effects that can limit their use. Consequently, the need for alternative anti-inflammatory treatments with high efficacy and safety profiles remains pressing. One potential approach is the inhalation of ultra-low doses of the alkylating agent melphalan. This article presents a clinical case illustrating the successful application of this novel therapeutic strategy in a patient with recurrent COP. KEYWORDS: cryptogenic organizing pneumonia, cytostatics, alkylating drugs, melphalan, treatment, inhalations. FOR CITATION: Sinitsyn E.A., Larchenko Yu.A., Samsonova M.V., Petrov K.S., Zykov K.A. Inhalation of ultra-low doses of alkylating drugs in a patient with recurrent cryptogenic organizing pneumonia. Russian Medical Inquiry. 2024;8(8):464–469 (in Russ.). DOI: 10.32364/2587- 6821-2024-8-8-4.

Novel indolyl 1,2,4-triazole derivatives as potential anti-proliferative agents: in silico studies, synthesis, and biological evaluation.

A new series of indolyl 1,2,4-triazole scaffolds was designed, synthesised, and biologically evaluated for their inhibitory activity against both CDK4 and CDK6. The results ranged from 0.049 μM to 3.031 μM on CDK4 and from 0.075 μM to 1.11 μM on CDK6 when compared to staurosporine, with IC50 values of 1.027 and 0.402 μM, respectively. Moreover, all compounds were tested for their cytotoxicity against two breast cancer cell lines, MCF-7 and MDA-MB-231. All of the synthesised compounds showed promising anti-proliferative activity, with two compounds Vf (IC50 = 2.91 and 1.914 μM, respectively) and Vg (IC50 = 0.891 and 3.479 μM, respectively) having potent cytotoxic activity in comparison to the reference staurosporine (IC50 = 3.144 and 4.385 μM, respectively). Vf and Vg were also found to significantly induce apoptosis to 45.33% and 37.26% (control = 1.91%) where Vf arrested the cell cycle at the S phase while Vg arrested the cycle at the G0/G1 phase. The binding mode and interactions of all compounds were studied and found to mimic those of the FDA approved CDK4/6 inhibitor palbociclib that was used as a reference throughout the study.

Benefits of a combined surgical technique for patients with secondary neovascular glaucoma.

Aim: To assess the effectiveness and safety of the proposed surgical technique for treating secondary neovascular glaucoma. Materials and Methods: We examined 28 eyes of 28 patients (16 women and 12 men), aged 46}7,2 years, with secondary neovascular glaucoma. All patients underwent a comprehensive ophthalmological examination before and during treatment. Two-stage treatment was applied to all patients. At the first stage - performed an advanced technique of non-penetrating deep sclerectomy while administering anti-VEGF (anti-vascular endothelial growth factor) intravitreal or intracameral injections. At the second - we performed externalization of Schlemm's canal followed by YAG laser trabeculectomy. Statistical analysis of the results was used the SPSS v. 11.0, MedStat v.15.1 software package for medical and biological research. Results: The proposed surgical technique, leads to a gradual decrease in intraocular pressure (IOP) and regression of the iris and anterior chamber angle neovascularization. The postoperative course was uneventful for all the patients. In the early postoperative period, the IOP was observed to be normalized in all the eyes. The IOP ranged from 12 to 16 mm Hg. The neovascularization regression occurred (in 100 % of cases) within 5-7 days. Conclusions: Gradual reduction of IOP reduces intraoperative complications. Intravitreal or intracameral injections of anti-proliferative agents contribute to the regression of neovascularization and further gradual reduction of IOP. Performing a laser trabeculectomy in the area where a non-penetrating deep sclerectomy was previously performed creates new pathways for the outflow of intraocular fluid from the anterior chamber and reduces the risks of reintervention.

Addressing Genetic Tumor Heterogeneity, Post-Therapy Metastatic Spread, Cancer Repopulation, and Development of Acquired Tumor Cell Resistance.

The concept of post-therapy metastatic spread, cancer repopulation and acquired tumor cell resistance (M-CRAC) rationalizes tumor progression because of tumor cell heterogeneity arising from post-therapy genetic damage and subsequent tissue repair mechanisms. Therapeutic strategies designed to specifically address M-CRAC involve tissue editing approaches, such as low-dose metronomic chemotherapy and the use of transcriptional modulators with or without targeted therapies. Notably, tumor tissue editing holds the potential to treat patients, who are refractory to or relapsing (r/r) after conventional chemotherapy, which is usually based on administering a maximum tolerable dose of a cytostatic drugs. Clinical trials enrolling patients with r/r malignancies, e.g., non-small cell lung cancer, Hodgkin's lymphoma, Langerhans cell histiocytosis and acute myelocytic leukemia, indicate that tissue editing approaches could yield tangible clinical benefit. In contrast to conventional chemotherapy or state-of-the-art precision medicine, tissue editing employs a multi-pronged approach targeting important drivers of M-CRAC across various tumor entities, thereby, simultaneously engaging tumor cell differentiation, immunomodulation, and inflammation control. In this review, we highlight the M-CRAC concept as a major factor in resistance to conventional cancer therapies and discusses tissue editing as a potential treatment.

Synthesis and pharmacological evaluation of novel coumarin based triazolyl glycoconjugates as potential antibacterial and anti-proliferative agents

Synthesis and pharmacological evaluation of novel coumarin based triazolyl glycoconjugates as potential antibacterial and anti-proliferative agents

Microwave-induced one-pot synthesis of 3-imidazolyl indole clubbed 1,2,3-triazole hybrids as antiproliferative agents and density functional theory study.

Herein, we outline a highly efficient PEG-4000-mediated one-pot three-component reaction for the synthesis of 3-imidazolyl indole clubbed 1,2,3-triazole derivatives (5a-r) at up to 96% yield as antiproliferative agents. This three-component protocol offers the advantages of an environmentally benign reaction, excellent yield, quick response time, and operational simplicity triggered by the copper catalyst under microwave irradiation. All the synthesized compounds were tested for antiproliferative activity against six human solid tumor cell lines, that is, A549 and SW1573 (nonsmall cell lung), HBL100 and T-47D (breast), HeLa (cervix), and WiDr (colon). Among them, six compounds, 5g-j, 5m, and 5p, demonstrated effective antiproliferative action with GI50 values under 10 μM. Furthermore, density functional theory (DFT) calculations were performed for all the synthesized molecules through geometry optimizations, frontier molecular orbital approach, and molecular electrostatic potential (MESP). The theoretical DFT calculation was performed using the DFT/B3LYP/6-31+G (d,p) basis set. Moreover, the biological reactivity of all the representative synthesized molecules was compared with the theoretically calculated quantum chemical descriptors and MESP 3D plots. We also investigated the drug-likeness characteristic and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction. In general, our approach enables environmentally friendly access to 3-imidazolyl indole clubbed 1,2,3-triazole derivatives as prospective antiproliferative agents.

New pyrrolidine-carboxamide derivatives as dual antiproliferative EGFR/CDK2 inhibitors.

Cancer is one of the leading causes of mortality worldwide, making it a public health concern. A novel series of pyrrolidine-carboxamide derivatives 7a-q were developed and examined in a cell viability assay utilizing a human mammary gland epithelial cell line (MCF-10A), where all the compounds exhibited no cytotoxic effects and more than 85% cell viability at a concentration of 50 μM. Antiproliferative activity was evaluated invitro against four panels of cancer cell lines A-549, MCF-7, Panc-1, and HT-29. Compounds 7e, 7g, 7k, 7n, and 7o were the most active as antiproliferative agents capable of triggering apoptosis. Compound 7g was the most potent of all the derivatives, with a mean IC50 of0.90 μM compared to IC50 of 1.10 μM for doxorubicin. Compound 7g inhibited A-549 (epithelial cancer cell line), MCF-7 (breast cancer cell line), and HT-29 (colon cancer cell line) more efficiently than doxorubicin. EGFR inhibitory assay results of 7e, 7g, 7k, 7n, and 7o demonstrated that the tested compounds inhibited EGFR with IC50 values ranging from 87 to 107 nM in comparison with the reference drug erlotinib (IC50 = 80 nM). 7e, 7g, 7k, 7n, and 7o inhibited CDK2 efficiently in comparison to the reference dinaciclib (IC50 = 20 nM), with IC50 values ranging from 15 to 31 nM. The results of inhibitory activity assay against different CDK isoforms revealed that the tested compounds had preferential inhibitory activity against the CDK2 isoform.

Thymol-Modified Oleic and Linoleic Acids Encapsulated in Polymeric Nanoparticles: Enhanced Bioactivity, Stability, and Biomedical Potential.

Unsaturated fatty acids, such as oleic acid (OA) and linoleic acid (LA), are promising antimicrobial and cytostatic agents. We modified OA and LA with thymol (TOA and TLA, respectively) to expand their bioavailability, stability, and possible applications, and encapsulated these derivatives in polymeric nanoparticles (TOA-NPs and TLA-NPs, respectively). Prior to synthesis, we performed mathematical simulations with PASS and ADMETlab 2.0 to predict the biological activity and pharmacokinetics of TOA and TLA. TOA and TLA were synthesized via esterification in the presence of catalysts. Next, we formulated nanoparticles using the single-emulsion solvent evaporation technique. We applied dynamic light scattering, Uv-vis spectroscopy, release studies under gastrointestinal (pH 1.2-6.8) and blood environment simulation conditions (pH 7.4), and in vitro biological activity testing to characterize the nanoparticles. PASS revealed that TOA and TLA have antimicrobial and anticancer therapeutic potential. ADMETlab 2.0 provided a rationale for TOA and TLA encapsulation. The nanoparticles had an average size of 212-227 nm, with a high encapsulation efficiency (71-93%), and released TOA and TLA in a gradual and prolonged mode. TLA-NPs possessed higher antibacterial activity against B. cereus and S. aureus and pronounced cytotoxic activity against MCF-7, K562, and A549 cell lines compared to TOA-NPs. Our findings expand the biomedical application of fatty acids and provide a basis for further in vivo evaluation of designed derivatives and formulations.