Hsp Inhibitor is Affective Against Adenocarcinomic Human Alveolar Basal Epithelial Cells Through Modulating ERK/MAPK Signaling Pathway.

The extracellular signal-regulated kinase (ERK) - mitogen-activated protein kinase (MAPK) pathway regulates cell proliferation, differentiation, and apoptosis. Heat Shock Protein 90 (HSP90) is required to activate proto-oncogenic protein kinases and promotes tumor growth through anti-apoptotic effects on A549-non-small cell lung cancer (NSCLC). Therefore, deregulation of the ERK-MAPK pathway and abnormal expression of HSP90 are reasonably frequent events in NSCLC. In this study, novel perimidine-pyrazole compounds employed to block ERK-MAPK deregulation through inhibiting HSP dependent cancer cell survival mechanisms. A set of perimidine-pyrazole derivatives effects was monitored on NSCLC cell line. Array experiments performed to understand the effect of the compounds on signaling pathways and results were analyzed by gene enrichment analysis. Further, senescence and apoptosis experiments were performed to support the enrichment results along with in silico methods to determine perimidine-pyrazole/HSP interactions. Treatment of NSCLC cells with perimidine-pyrazole derivatives displayed cancer-inhibitory, pro-senescent and pro-apoptotic effects on NSCLC cells through ERK/MAPK pathway and these compounds are promising templates for designing anticancer drugs.

Synthesis and biological studies of pyrimidine derivatives targeting metabolic enzymes.

Novel synthesized pyrimidine derivatives were investigated against carbonic anhydrase isoenzymes I and II (hCA I and II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-glycosidase, and aldose reductase (AR) enzymes associated with some common diseases such as epilepsy, glaucoma, Alzheimer's disease, diabetes, and neuropathy. When the results were examined, novel synthesized pyrimidine derivatives were found to have effective inhibition abilities toward the metabolic enzymes. IC50 values and Ki values were calculated for each pyrimidine derivative and compared to positive controls. The synthesized novel pyrimidine derivatives exhibited Ki values in the range of 39.16 ± 7.70-144.62 ± 26.98 nM against hCA I, 18.21 ± 3.66-136.35 ± 21.48 nM toward hCA II, which is associated with different pathological and physiological processes, 33.15 ± 4.85-52.98 ± 19.86 nM on AChE, and 31.96 ± 8.24-69.57 ± 21.27 nM on BChE. Also, Ki values were determined in the range of 17.37 ± 1.11-253.88 ± 39.91 nM against α-glycosidase and 648.82 ± 53.74-1902.58 ± 98.90 nM toward AR enzymes. Within the scope of the study, the inhibition types of the novel synthesized pyrimidine derivatives were evaluated.

Discovery of sulfadrug-pyrrole conjugates as carbonic anhydrase and acetylcholinesterase inhibitors.

Human carbonic anhydrase (hCA) isoenzymes are zinc ion-containing, widespread metalloenzymes and they classically play a role in pH homeostasis maintenance. CA inhibitors suppress the CA activity and their usage has been clinically established as antiglaucoma agents, antiepileptics, diuretics, and in some other disorders. Alzheimer's disease (AD) is a slowly progressive neurodegenerative disorder and a fatal disease of the brain. An advanced method to cure AD includes the strategy to design acetylcholinesterase (AChE) inhibitors. A novel series of pyrrole-3-one derivatives containing sulfa drugs (5a-i) were determined to be highly potent inhibitors for AChE and hCA I and hCA II (inhibitory constant [Ki ] values are in the range of 6.50 ± 1.02-37.46 ± 4.12 nM, 1.20 ± 0.19-44.21 ± 1.09 nM, and 8.93 ± 1.58-46.86 ± 8.41 nM for AChE, hCA I, and hCA II, respectively). The designed compounds often show a more effective inhibition than the chemicals used as the standard. Among these compounds, 5f was the most effective compound against hCA I, and compound 5e was the most effective compound against hCA II. It was determined that compound 5c was the most effective inhibitor for AChE.

The Comparison of the Biological Rhythms of Patients with Fibromyalgia Syndrome with Biological Rhythms of Healthy Controls.

BACKGROUND Fibromyalgia syndrome (FMS) is a rheumatic disease characterized by diffuse body pain and decreased muscle function. The aim of the present study was to compare the biological rhythms of patients with fibromyalgia syndrome with the biological rhythms of healthy controls. MATERIAL AND METHODS This was a cross-sectional, single blind, and single center case-control study. The patients with fibromyalgia were evaluated using a Fibromyalgia Impact Questionnaire (FIQ), Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) Scale, Visual Analog Scale (VAS), Pittsburg Sleep Quality Index (PSQI) and Beck Depression Inventory (BDI). RESULTS The study included 77 female patients with FMS, and 32 healthy female individuals as the control group. We found that the patients in the FMS group achieved higher scores in VAS, BDI, PSQI, and the BRIAN scale than the patients in the control group (P<0.001). An evaluation of the relationship between FMS evaluation parameters and biological rhythm scores in patients with FMS revealed a significant positive correlation between total BRAIN and VAS, FIQ, BDI, and PSQI scores. When the relationship between FMS evaluation parameters and biological rhythm scores was evaluated in patients with FMS, a significant positive correlation was found between total BRAIN and VAS, FIQ, BDI, and PSQI scores (r=0.555, P<0.001; r=0.461, P<0.001; r=0.630, P<0.001; and r=0.551, P<0.001 respectively). CONCLUSIONS We consider that an evaluation of the biological rhythm of female patients with FMS, and appropriate treatment when required, would contribute significantly to the treatment and follow-up process of the patients.

Assessment of the effectiveness of interferential current therapy and TENS in the management of carpal tunnel syndrome: a randomized controlled study.

We assessed the effectiveness of interferential current (IFC) and transcutaneous electrical nerve stimulation (TENS) therapies in the management of carpal tunnel syndrome (CTS) compared with splint therapy, a standard treatment modality for CTS. This was a prospective, single-blinded, single-center, randomized, three-group parallel intervention study of 3 weeks duration. Efficacy was examined in the third week after the end of treatments. Subjects were assigned randomly to one of three groups: group I patients received splint therapy, group II patients received TENS applied on the palmar surface of the hand and the carpal tunnel, and group III patients underwent IFC therapy applied on the palmar surface of the hand and the volar surface of the forearm. TENS and ICF treatments were applied five times weekly for a total of 15 sessions. Group 1 patients were stabilized with volar wrist splints for 3 weeks. The efficacy of the therapies was assessed before initiation of therapy and at 3 weeks after completion of therapy using a visual analog scale (VAS), a symptom severity scale, the functional capacity scale of the BCTQ, and measurement of median nerve motor distal latency (mMDL) and median sensory nerve conduction velocity (mSNCV). Groups were compared pairwise using the Mann-Whitney U test to identify the source of differences between groups. The Wilcoxon test was used to analyze changes in variables over time within a group. In the VAS, BCTQ, MDL, and mSNCV, no significant difference was observed between the groups (p > 0.05). In the VAS, BCTQ, and mSNCV, statistically significant improvements were detected in all groups (p < 0.05). There was no statistically significant difference between TENS and splint therapy with respect to improvement in clinical scores, whereas IFC therapy provided a significantly greater improvement in VAS, mMDL, and mSNCV values than splint therapy (VAS: 4.80 ± 1.18 and 6.37 ± 1.18; p = 0.001, mMDL: 3.89 ± 0.88 and 4.06 ± 0.61; p = 0.001, mSNCV: 41.80 ± 1.76 and 40.75 ± 1.48; p = 0.010). IFC therapy provided a significantly greater improvement in VAS, symptom severity, functional capacity, and mMDL and mSNCV values than TENS therapy (VAS: 4.80 ± 1.18 and 6.68 ± 1.42; p < 0.001, symptom severity: 2.70 ± 1.03 and 3.37 ± 1.21; p = 0.015, functional capacity: 1.90 ± 1.21 and 2.50 ± 0.78; p = 0.039, mMDL: 3.89 ± 0.88 and 4.06 ± 0.88; p = 0.003, and mSNCV: 41.80 ± 1.76 and 41.38 ± 1.78; p = 0.021). IFC may be considered a new and safe therapeutic option for the treatment of CTS.

Quality of life, depression, and sexual dysfunction in spouses of female patients with fibromyalgia.

The aim of this study was to investigate the effects of the quality of life and psychological condition of female patients with fibromyalgia and their spouses on sexual function. A total of 32 female patients diagnosed with fibromyalgia and their spouses were analyzed. Thirty married couples were included in the study as the control group. The demographic data of the fibromyalgia patients were recorded, a visual analog scale was used to evaluate the level of pain, and the Fibromyalgia Impact Questionnaire was used to evaluate the impact of the symptoms on the quality of life of the patients. The quality of life of both the patients and the control group were evaluated using the Short Form 36 (SF-36), and psychological variables were evaluated using the Beck Depression Inventory (BDI) and Beck Anxiety Inventory. Sexual function was assessed using the Female Sexual Function Index for female participants and the International Index of Erectile Function (IIEF) for male participants. The IIEF erectile dysfunction scores were significantly lower in the spouses of female patients with fibromyalgia than in the control group (p < 0.05), and the BDI scores were significantly higher in the spouses of the female patients with fibromyalgia (p < 0.05). Among the SF-36 scores, the emotional and physical roles were significantly lower in the spouses of the female patients with fibromyalgia (p = 0.003 and p = 0.004, respectively). In all spouses of FMS patients and controls, there was a significantly negative correlation between erectile function, the BDI score, and to be married with FMS patient and positive correlations between erectile function and emotional role, social function, mental health, SF-36 pain score, and general health (p < 0.05 for all). In a linear regression model, BDI, to be married with FMS patient and general health were found to affect erectile function (beta regression coefficient = -0.572, SE = 0.082, p = 0.001; beta regression coefficient = -0.332, SE = 1.619, p = 0.007; beta regression coefficient = 0.445, SE = 0.065, p = 0.005, respectively). Being a spouse of a patient with fibromyalgia might significantly interfere with quality of life and lead to a high rate of sexual dysfunction. Spouses of patients with fibromyalgia might also be investigated for sexual dysfunction and quality of life. Treatment programs for this group should be considered.

A comparison of the effectiveness of low-, moderate- and high-dose ultrasound therapy applied in the treatment of myofascial pain syndrome.

OBJECTIVE: This study aimed to compare and evaluate the effects of ultrasound (US) treatment applied at low-, medium- and high-power-pain threshold (HPPT) doses to trigger points in the treatment of myofascial pain syndrome (MPS). METHODS: The study comprised 61 (40 female and 21 male) patients diagnosed with MPS, aged between 18 and 60 years. The patients were randomly allocated to three groups for the US application at different dosages. Group I patients received treatment of medium-dose US (1.5 Watt/cm(2)), Group II received HPPT US, and Group III received low-dose US (0.5 W/cm(2)). The patients were evaluated pre-treatment and 3 weeks after treatment in respect of visual analogue scale (VAS) scores, number of trigger points (NTP), pressure pain threshold (PPT), Range of Tragus-Acromioclavicular joint (RT-AJ) and neck pain disability scores (NPDS). RESULTS: A significant improvement was determined after treatment in all scores except PPT in Group I, in all scores in Group II, and only in the VAS score in Group III. When the groups were compared post-treatment in respect of improvement in NTP, VAS, RT-AJ and NPDS scores, Group II showed significant superiority over Group I, and Group I was determined to have significant superiority over Group III in respect of VAS, RT-AJ and NPDS scores (p < 0.05). CONCLUSIONS: In the treatment of MPS, US therapy at HPPT dose can be considered as an alternative therapy method, which is more economical and more effective than low-dose and conventional US therapy.

An evaluation of oxidative stress and antioxidant capacity in patients with myofascial pain syndrome.

OBJECTIVE: To evaluate total antioxidant capacity (TAC) and total oxidative stress (TOS) values in patients with myofascial pain syndrome (MPS). METHOD: The study comprised 38 patients diagnosed with MPS and 30 healthy volunteers. The age, body mass index (BMI) and pain scores (evaluation by visual analogue scales) of all the participants were recorded. The TAC, TOS and oxidative stress index (OSI) levels were compared between the MPS and control groups. RESULTS: There was no significant difference between the MPS and control groups in respect of demographic characteristics. The TAC levels were determined to be significantly lower and TOS levels and OSI values, significantly higher in the MPS patients than in the control group. CONCLUSION: The results of this study determined that the oxidant/antioxidant balance was impaired in MPS patients and thus MPS can be considered to be related to an increase in oxidative stress.

The Relationship between Quadriceps Thickness, Radiological Staging, and Clinical Parameters in Knee Osteoarthritis.

[Purpose] The aim of this study was to investigate the relationship between clinical parameters, radiological staging and evaluated ultrasound results of quadriceps muscle thickness in knee osteoarthritis. [Subjects] The current study comprised 75 patients (51 female, 24 male) with a mean age of 57.9±5.2 years (range 40-65 years) and a diagnosis of osteoarthritis in both knees. [Methods] Knee radiographs were evaluated according to the Kellgren-Lawrence grading system. Clinical evaluation performed with the visual analog scale (VAS), Western Ontario and McMaster Osteoarthritis Index (WOMAC), the 50-meter walking test, and the 10-step stair test. The thickness of the muscle layer of the quadriceps femoris (M. vastus intermedius and M. rectus femoris) was measured with high-resolution real-time ultrasonography. [Results] The results of this study showed a significant negative correlation between quadriceps thickness and age, duration of disease, stage of knee OA, and VAS, WOMAC, 50-m walking test, and 10-step stair test scores. [Conclusion] The evaluation of quadriceps muscle thickness with ultrasound can be considered a practical and economical method in the diagnosis and follow-up of knee osteoarthritis.

Is There Any Relationship between Joint Destruction and Carotid Intima-media Thickness in Patients with Rheumatoid Arthritis?

[Purpose] The purpose of this study was to investigate the possible relationship between joint destruction and carotid intima-media thickness in patients with rheumatoid arthritis. [Subjects and Methods] Thirty-four RA patients and 31 healthy controls were enrolled in this study. The disease activity for 28 joints was recorded for each patient using the erythrocyte sedimentation rate (DAS28ESR), a visual analog scale (VAS0-10 cm), and a disability index, the health assessment questionnaire (HAQ). X-ray imagesof the patients were scored according to the modified Sharp/van der Heijde method, and the common carotid intimal medial thickness (CIMT) was automatically measured with software using high-resolution Doppler ultrasound. [Results] Contrary to our hypothesis, the modified total Sharp score (mTSS) and CIMT were not significantly associated. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels of the RA patients and the right CIMT, left CIMT, and mean CIMT scores were significantly elevated. Positive correlation was detected between the mean CIMT score and age, CRP levels, LDL concentration and triglycerides (TG) level. In the regression model, where the mean CIMT was the independent variable and age, CRP, LDL, and TG were dependent variables, age was found to be an independent predictor of CIMT. [Conclusions] Patients suffering from RA require close monitoring for cardiovascular risks, and the comorbidity of age-related cardiovascular disease should not be overlooked.

Relationship among Ocular Diseases, Developmental Levels, and Clinical Characteristics of Children with Diplegic Cerebral Palsy.

[Purpose] The aim of this study was to evaluate the relationships among vision problems, developmental levels, upper extremity functions, and qualities of life of children with cerebral palsy (CP). [Subjects] The study included 32 children, aged 4-15 years, diagnosed with diplegic type CP. [Methods] Hand function was evaluated using the Manual Ability Classification System (MACS) and the Bimanual Fine Motor Function (BFMF) scale, and the severity of CP was assessed using the Gross Motor Function Classification System (GMFCS). The developmental and mental capabilities of the children were evaluated using the Ankara Developmental Screening Inventory (ADSI) or the WISC-R test. An oculomotor examination was conducted for all patients. [Results] Positive correlations were found between GMFCS and BFMF, GMFCS and MACS, and MACS and BFMF scores (r=0.636; r=0.553; r=0.718, respectively). Significant correlations were found between upper extremity function, the severity of CP, the quality of life, and the general developmental level. There was no significant correlation between ocular disorders and clinical characteristics. [Conclusion] GMFCS, MACS, and BFMF may be useful for defining the functional status of children with CP, as they are easy, practical, and simple classification scales that conform to each other.

Effectiveness of a home exercise program in combination with ultrasound therapy for temporomandibular joint disorders.

[Purpose] This study compared the effectiveness of home exercise alone versus home exercise combined with ultrasound for patients with temporomandibular joint disorders. [Subjects and Methods] This study enrolled 23 female and 15 male patients who were divided randomly into two groups. The home exercise group performed a home exercise program consisting of an exercise program and patient education, and the home exercise combined with ultrasound group received ultrasound therapy in addition to the home exercise program. Pain intensity was evaluated using a visual analogue scale. Pain free maximum mouth opening was evaluated at baseline and 2 weeks after the treatment. [Results] There was no difference between the two groups in baseline values. After the treatment, the visual analogue scale decreased and pain free maximum mouth opening scores improved significantly in each group. Additionally, both values were higher in the home exercise combined with ultrasound group than in the home exercise group. [Conclusion] The combination of home exercise combined with ultrasound appears to be more effective at providing pain relief and increasing mouth opening than does home exercise alone for patients with temporomandibular joint disorders.

Evaluation of open and closed kinetic chain exercises in rehabilitation following anterior cruciate ligament reconstruction.

[Purpose] To compare outcomes of anterior cruciate ligament (ACL) reconstruction after open kinetic chain (OKC) exercises and closed kinetic chain (CKC) exercises. [Subjects and Methods] The subjects comprised 11 female and 47 male patients who are randomly divided into two groups: which performed a CKC exercise program Group I and Group II which performed an OKC exercise program. Pain intensity was evaluated using visual analogue scale (VAS). Knee flexion was evaluated using a universal goniometer, and thigh circumference measurements were taken with a tape measure at baseline and at 3 months and 6 months after the treatment. Lysholm scores were used to assess knee function. [Results] There were no significant differences between the two groups at baseline. Within each group, VAS values and knee flexion were improved after the surgery. These improvements were significantly higher in the CKC group than in the OKC group. There were increases in thigh circumference difference at the 3 and 6 month assessments post-surgery. A greater improvement in the Lysholm score was observed in the CKC group at 6 months. [Conclusion] The CKC exercise program was more effective than OKC in improving the knee functions of patients with ACL reconstruction.

Deciphering the Biophysical Properties of Ion Channel Gating Pores by Coumarin-Benzodiazepine Hybrid Derivatives: Selective AMPA Receptor Antagonists.

In the 1980s, the identification of specific pharmacological antagonists played a crucial role in enhancing our comprehension of the physiological mechanisms associated with α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs). The primary objective of this investigation was to identify specific AMPA receptor antagonists, namely 2,3-benzodiazepines, that function as negative allosteric modulators (NAMs) at distinct locations apart from the glutamate recognition site. These compounds have exhibited a diverse array of anticonvulsant properties. In order to conduct a more comprehensive investigation, the study utilized whole-cell patch-clamp electrophysiology to analyze the inhibitory effect and selectivity of benzodiazepine derivatives that incorporate coumarin rings in relation to AMPA receptors. The study's main objective was to acquire knowledge about the relationship between the structure and activity of the compound and comprehend the potential effects of altering the side chains on negative allosteric modulation. The investigation provided crucial insights into the interaction between eight CD compounds and AMPA receptor subunits. Although all compounds demonstrated effective blockade, CD8 demonstrated the greatest potency and selectivity towards AMPA receptor subunits. The deactivation and desensitization rates were significantly influenced by CD8, CD6, and CD5, distinguishing them from the remaining five chemicals. The differences in binding and inhibition of AMPA receptor subunits can be attributed to structural discrepancies among the compounds. The carboxyl group of CD8, situated at the para position of the phenyl ring, substantially influenced the augmentation of AMPA receptor affinity. The findings of this study highlight the potential of pharmaceutical compounds that specifically target AMPA receptors to facilitate negative allosteric modulation.

Synthesis of novel carbazole hydrazine-carbothioamide scaffold as potent antioxidant, anticancer and antimicrobial agents.

BACKGROUND: Carbazole-based molecules containing thiosemicarbazide functional groups are recognized for their diverse biological activities, particularly in enhancing therapeutic anticancer effects through inhibiting crucial pathways. These derivatives also exhibit noteworthy antioxidant properties. OBJECTIVES: This study aims to synthesize, characterize, and evaluate the antioxidant and anticancer activities of 18 novel carbazole derivatives. METHODS: The radical scavenging capabilities of the compounds were assessed using the 2,2-diphenyl-1-picrylhydrazyl assay. Antiproliferative activities were evaluated on MCF-7 cancer cell lines through viability assays. Additionally, the modulation of the PI3K/Akt/mTOR pathway, apoptosis/necrosis induction, and cell cycle analysis were conducted for the most promising anticancer agents. RESULTS: nine compounds showed potent antioxidant activities with IC50 values lower than the positive control acarbose, with compounds 4 h and 4y exhibiting the highest potency (IC50 values of 0.73 and 0.38 µM, respectively). Furthermore, compounds 4o and 4r displayed significant anticancer effects, with IC50 values of 2.02 and 4.99 µM, respectively. Compound 4o, in particular, exhibited promising activity by targeting the PI3K/Akt/mTOR signaling pathway, inhibiting tumor survival, inducing apoptosis, and causing cell cycle arrest in MCF-7 cell lines. Furthermore, compound 4o was showed significant antimicrobial activities against S. aureus and E. coli, and antifungal effect against C. albicans. Its potential to overcome drug resistance through this pathway inhibition highlights its promise as an anticancer agent. Molecular docking simulations supported these findings, revealing favorable binding profiles and interactions within the active sites of the enzymes PI3K, AKT1, and mTOR. Moreover, assessing the druggability of the newly synthesized thiosemicarbazide derivatives demonstrated optimal physicochemical properties, further endorsing their potential as drug candidates.

Synthesis and anticancer activity of acyl thioureas bearing pyrazole moiety.

In this work novel organic based compounds, acyl thiourea derivatives were synthesized and their anticancer activities were investigated. A new series of acyl thiourea derivatives containing pyrazole ring were prepared in good yield through one pot reaction of 4-benzoyl-1, 5-diphenyl-1H-pyrazole-3-carbonyl chloride with ammonium thiocyanate and various amines. The structures of the newly synthesized compounds were confirmed by IR, (1)H NMR, (13)C NMR and elemental analysis. Anticancer activities of synthesized compounds were evaluated on human colon, liver and leukemia cancer cell lines. Cell culture studies have demonstrated significant toxicity of the compounds on the cell lines, and the levels of toxicity have altered in the presence of various side groups. These results confirm that novel pyrazolyl acyl thioureas derived compounds may be utilized for cancer treatment. Furthermore, these compounds have a great potential and significance for further investigations.

Comparison of the efficacy of ketoprofen phonophoresis, ultrasound, and short-wave diathermy in knee osteoarthritis.

The present study aimed to compare the efficacy of three different deep heating modalities: phonophoresis (PH), short-wave diathermy (SWD), and ultrasound (US), in knee osteoarthritis. Patients who consented to participate in the study were randomly divided into the following three groups. Group 1 (n = 33) received PH, Group 2 (n = 33) received US, and Group 3 (n = 35) received SWD. These deep heating therapies were applied by the same therapist. Each therapy began with 20-min hot pack application. Each of the three physical therapy modalities was applied 5 days a week for 2 weeks (a total of 10 sessions). The patients were evaluated using visual analogue scale (VAS) at rest, 15-m walking time, and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) both before and after the treatment. Moreover, at the end of the treatment, both the physician and the patient made an overall evaluation, by rating the treatment efficacy. The results of the study showed that VAS, 15-m walking time, and WOMAC parameters were improved with all three deep heating modalities, and all the three modalities were effective. However, there was no significant difference between the three modalities in terms of efficacy. There was also no significant difference between the three groups in terms of post-treatment general evaluation of the physician and the patient. The present study is the first to suggest that choosing one of PH/US/SWD therapy options would provide effective results and none of them are superior to the others, and we believe that these findings will be a basis for further studies.

Design, synthesis, molecular docking and biological evaluation of new carbazole derivatives as anticancer, and antioxidant agents.

BACKGROUND: The carbazole skeleton is an important structural motif occurring naturally or synthesized chemically and has antihistaminic, antioxidant, antitumor, antimicrobial, and anti-inflammatory activities. OBJECTIVES: This study aimed to design and synthesize a novel series of carbazole derivatives and evaluate their antiproliferative and antioxidant activities. METHODS: The synthesized compounds were characterized utilizing HRMS, 1H-, and 13CAPT-NMR, and assessed for their anticancer, antifibrotic, and antioxidant effects utilizing reference biomedical procedures. In addition, the AutoDock Vina application was used to perform in-silico docking computations. RESULTS: A series of carbazole derivatives were synthesized and characterized in the current study. Compounds 10 and 11 were found to have a stronger antiproliferative effect than compounds 2-5 against HepG2, HeLa, and MCF7 cancer cell lines with IC50 values of 7.68, 10.09, and 6.44 µM, respectively. Moreover, compound 9 showed potent antiproliferative activity against HeLa cancer cell lines with an IC50 value of 7.59 µM. However, except for compound 5, all of the synthesized compounds showed moderate antiproliferative activities against CaCo-2 with IC50 values in the range of 43.7-187.23 µM. All of these values were compared with the positive control anticancer drug 5-Fluorouracil (5-FU). In addition, compound 9 showed the most potent anti-fibrotic compound, and the cellular viability of LX-2 was found 57.96% at 1 µM concentration in comparison with the positive control 5-FU. Moreover, 4 and 9 compounds showed potent antioxidant activities with IC50 values of 1.05 ± 0.77 and 5.15 ± 1.01 µM, respectively. CONCLUSION: Most of the synthesized carbazole derivatives showed promising antiproliferative, antioxidant, and antifibrotic biological effects, and further in-vivo investigations are needed to approve or disapprove these results.

Synthesis, molecular docking, molecular dynamics and evaluation of Drug-Likeness properties of the fused N-Formyl pyrazoline substituted new dehydroepiandrosterone derivatives.

The hybrid molecules bearing heterocyclic structures in the A or D rings of steroids have significant biological activity. 16 (E)-Hetereoarylidene steroids were synthesized from the reaction of different heteroaromatic carbaldehydes and trans-Dehydroepiandrosterone (DHEA) in a basic medium. Then, synthesis of the N-formyl pyrazoline substituted new DHEA derivatives were carried out from the reaction of hydrazine hydrate and 16 (E)-hetereoarylidene steroids. The structures of the synthesized compounds were elucidated by elemental analysis, FT-IR, 1H NMR, and 13C NMR spectroscopy. To investigate the activation pathway of synthesized N-formyl pyrazoline substituted steroid derivatives, a molecular docking study was performed on human cytochrome P450-(CYP17A1: PDB ID 5IRQ) with the help of the free AutoDock Vina. 100 ns molecular dynamic simulation process was performed to monitor the behavior of the complex structure formed by CYP17A1 and to calculate the stability over time of 2a and 2d (-9.8 kcal/mol), which gave the lowest value according to the results obtained in the molecular docking study with AutoDock Vina. Accordingly, RMSD, RMSF, Rg, and SASA analyzes of 2a and 2d were performed, and MMPBSA was calculated. Lastly, the ADMET (absorption, distribution, metabolism, excretion, and toxicity) analyses of the novel steroid derivatives were investigated.Communicated by Ramaswamy H. Sarma.

Triad pyrazole-thiazole-coumarin heterocyclic core effectively inhibit HSP and drive cancer cells to apoptosis.

Intensive studies on hepatocellular carcinoma (HCC), which is spreading rapidly around the world and has a high mortality rate, is due to the lack of adequate preventive or curative treatment methods. Treating patients with HCC has become very challenging because of the heterogeneity in the patient population lead activation of different signaling pathways, and pathway crosstalk for patients. Therefore, understanding these molecular mechanisms and combining drugs with molecular therapies to overcome these drawbacks has become an area of utmost importance. In this study, the biological activities of the designed and characterized triad Pyrazole-Thiazol-Coumarin (PTC) compounds were determined by performing cell viability, qPCR array, apoptosis and cell cycle assays. One of the compounds (PTC10) implicitly suppresses multiple pathways (RAS/MAP kinase and PI3K-AKT) simultaneously. This action is provided by (i) arresting cancer cells at G2 phase, (ii) driving cancer cells to apoptosis and (iii) inhibiting HSP network. Remarkably, HSP is an apoptotic factor and help cancer cell to survive. HSP90 also coordinates with Cdk4/Cdc37, therefore inhibiting HSP both drives cells to arrest and apoptosis. ATP hydrolysis and aggregation assay further displayed specific HSP inhibition. Therefore, PTC provides a unique drug template for HCC treatment.