Design, synthesis, in silico and biological evaluation of new indole based oxadiazole derivatives targeting estrogen receptor alpha.

A series of new indole-oxadiazole derivatives was designed and synthesized to develop potential anti-breast cancer agents. The compounds exhibited significant inhibitory activity with IC50 values ranging from 1.78 to 19.74 µM against ER-positive human breast cancer (BC) cell lines T-47D and MCF-7. Among them, compounds (5a, 5c, 5e-5h, 5j-5o) displayed superior activity against ER-α dominant (ratio of ER-α/ER-ß is 9/1) T-47D cells compared to the standard drug bazedoxifene (IC50 = 12.78 ± 0.92 µM). Compounds 5c and 5o exhibited remarkable anti-proliferative activity with IC50 values of 3.24 ± 0.46 and 1.72 ± 1.67 µM against T-47D cells, respectively. Further, compound 5o manifested 1589-fold higher ER-α binding affinity (213.4 pM) relative to bazedoxifene (339.2 nM) in a competitive ER-α binding assay, while compound 5c showed a binding affinity of 446.6 nM. The Western blot analysis proved that both compounds influenced the ER-α protein's expression, impeding its subsequent transactivation and signalling pathway within T-47D cells. Additionally, a molecular docking study suggests that compounds 5c and 5o bind in such a fashion that induces conformational changes in the protein, culminating in their antagonistic effect. Also, pharmacokinetic profiles showed that all compounds have drug-like properties. Further, molecular dynamic (MD) simulations and density functional theory (DFT) analysis confirmed the stability, conformational behaviour, reactivity, and biological feasibility of compounds 5c and 5o. In conclusion, based on our findings, compounds 5c and 5o, which exhibit significant ER-α antagonistic activity, can act as potential lead compounds for developing anti-breast cancer agents.

Design, synthesis, in vitro and in silico evaluation of indole-based tetrazole derivatives as putative anti-breast cancer agents.

A series of new indole-tetrazole derivatives were designed and synthesized to develop potential anti-breast cancer agents. The compounds exhibited in vitro anti-proliferative activity against ER-α positive T-47D (IC50 = 3.82-24.43 µM), MCF-7 (IC50 = 3.08-22.65 µM), and ER-α negative MDA-MB-231 (IC50 = 7.69-19.4 µM) human breast cancer cell lines. Compounds 5d and 5f displayed significant anti-proliferative activity compared to bazedoxifene (IC50 = 14.23 ± 0.68 µM), with IC50 values of 10.00 ± 0.59 and 3.83 ± 0.74 µM, respectively, against the ER-α dominant T-47D cell line. Also, both compounds showed non-significant cytotoxicity against normal cells HEK-293. Further, the ER-α binding affinity of 5d and 5f was assessed through a fluorescence polarization-based competitive binding assay, where 5d and 5f have shown significant binding with IC50 = 5.826 and 110.6 nM, respectively, as compared to the standard drug bazedoxifene (IC50 = 339.2 nM). Western blot analysis confirmed that compound 5d reduced ER-α protein expression in T-47D cells, hindering its transactivation and signalling pathways. Additionally, a molecular docking study suggests that compounds 5d and 5f bind in such a fashion that induces conformational changes in the protein, culminating in their antagonistic effect. Pharmacokinetic profiles showed that the compounds possessed drug-like properties. Furthermore, molecular dynamics simulation studies establish the dynamic stability and conformational behaviour of the ER-α protein and ligand complex of both compounds. Additionally, 5d and 5f ensure biological feasibility as per their DFT analysis through HOMO-LUMO energy gap analysis. In conclusion, compounds 5d and 5f, exhibiting significant ER-α antagonistic activity, can act as potential lead compounds for anti-breast cancer therapies.

Synthesis, and In-silico Studies of Indole-chalcone Derivatives Targeting Estrogen Receptor Alpha (ER-α) for Breast Cancer.

BACKGROUND: Breast cancer is the prominent reason of death in women worldwide, and the cases are increasing day by day. There are many FDA-approved drugs for treating breast cancer. Due to drug resistance, and problems in selectivity, there is a need to develop more effective agents with few side effects. Indole derivatives have demonstrated significant pharmacological potential as anti-breast cancer agents. Further, chalcone derivatives incorporating heterocyclic scaffolds play a significant role in medicine. Indole-chalcone-based compounds offer the potential for improved biological activity and enhanced drug-like properties. It prompted us to explore the synthesis of Indole-Chalcone derivatives targeting estrogen receptor alpha (ER-α) to discover potent anti-breast cancer agents. OBJECTIVES: To synthesize indole-chalcone derivatives and study their binding interactions for ER-α protein by molecular docking for breast cancer treatment. METHODS: In this study, indole-chalcone derivatives have been synthesized using conventional heating. With the help of Schrodinger software, molecular interaction as well as ADME (Adsorption, Distribution, Metabolism, and Excretion) studies of the compounds were conducted. RESULTS: Among all the synthesized compounds, four compounds (1, 2, 3, and 4) showed better docking scores (-10.24 kcal/mol, -10.15 kcal/mol, -9.40 kcal/mol, -9.29 kcal/mol, respectively) than the standard tamoxifen (-8.43 kcal/mol). CONCLUSION: From In-silico studies, we can conclude that four compounds from the synthesized series fit into the active site of ER-α. ADME properties of synthesized derivatives were found in the acceptable range. In the future, these compounds can be further explored for biological activity.

Biophysical characterization of chloride intracellular channel 6 (CLIC6).

Chloride intracellular channels (CLICs) are a family of proteins that exist in soluble and transmembrane forms. The newest discovered member of the family CLIC6 is implicated in breast, ovarian, lung gastric, and pancreatic cancers and is also known to interact with dopamine-(D(2)-like) receptors. The soluble structure of the channel has been resolved, but the exact physiological role of CLIC6, biophysical characterization, and the membrane structure remain unknown. Here, we aimed to characterize the biophysical properties of this channel using a patch-clamp approach. To determine the biophysical properties of CLIC6, we expressed CLIC6 in HEK-293 cells. On ectopic expression, CLIC6 localizes to the plasma membrane of HEK-293 cells. We established the biophysical properties of CLIC6 by using electrophysiological approaches. Using various anions and potassium (K+) solutions, we determined that CLIC6 is more permeable to chloride-(Cl-) as compared to bromide-(Br-), fluoride-(F-), and K+ ions. In the whole-cell configuration, the CLIC6 currents were inhibited after the addition of 10 µM of IAA-94 (CLIC-specific blocker). CLIC6 was also found to be regulated by pH and redox potential. We demonstrate that the histidine residue at 648 (H648) in the C terminus and cysteine residue in the N terminus (C487) are directly involved in the pH-induced conformational change and redox regulation of CLIC6, respectively. Using qRT-PCR, we identified that CLIC6 is most abundant in the lung and brain, and we recorded the CLIC6 current in mouse lung epithelial cells. Overall, we have determined the biophysical properties of CLIC6 and established it as a Cl- channel.

The genetic variability of grapevine Pinot gris virus (GPGV) in Australia.

Grapevine Pinot gris virus (GPGV; genus Trichovirus in the family Betaflexiviridae) was detected in Australia in 2016, but its impact on the production of nursery material and fruit in Australia is still currently unknown. This study investigated the prevalence and genetic diversity of GPGV in Australia. GPGV was detected by reverse transcription-polymerase chain reaction (RT-PCR) in a range of rootstock, table and wine grape varieties from New South Wales, South Australia, and Victoria, with 473/2171 (21.8%) samples found to be infected. Genomes of 32 Australian GPGV isolates were sequenced and many of the isolates shared high nucleotide homology. Phylogenetic and haplotype analyses demonstrated that there were four distinct clades amongst the 32 Australian GPGV isolates and that there were likely to have been at least five separate introductions of the virus into Australia. Recombination and haplotype analysis indicate the emergence of new GPGV strains after introduction into Australia. When compared with 168 overseas GPGV isolates, the analyses suggest that the most likely origin of Australian GPGV isolates is from Europe. There was no correlation between specific GPGV genotypes and symptoms such as leaf mottling, leaf deformation, and shoot stunting, which were observed in some vineyards, and the virus was frequently found in symptomless grapevines.

Identification of 1,3,4-oxadiazoles as tubulin-targeted anticancer agents: a combined field-based 3D-QSAR, pharmacophore model-based virtual screening, molecular docking, molecular dynamics simulation, and density functional theory calculation approach.

Cancer is one of the most prominent causes of death worldwide and tubulin is a crucial protein of cytoskeleton that maintains essential cellular functions including cell division as well as cell signalling, that makes an attractive drug target for cancer drug development. 1,3,4-oxadiazoles disrupt microtubule causing G2-M phase cell cycle arrest and provide anti-proliferative effect. In this study, field-based 3D-QSAR models were developed using 62 bioactive anti-tubulin 1,3,4-oxadiazoles. The best model characterized by PLS factor 7 was rigorously validated using various statistical parameters. Generated 3D-QSAR model having high degree of confidence showed favourable and unfavourable contours around 1,3,4-oxadiazole core that assisted in defining proper spatial positioning of desired functional groups for better bioactivity. A five featured pharmacophore model (AAHHR_1) was developed using same ligand library and validated through enrichment analysis (BEDROC160.9 value = 0.59, Average EF 1% = 27.05, and AUC = 0.74). Total 30,212 derivatives of 1,3,4-oxadiazole obtained from PubChem database was prefiltered through validated pharmacophore model and docked in XP mode on binding cavity of tubulin protein (PDB code: 1SA0) which led into the identification of 11 HITs having docking scores between -7.530 and -9.719 kcal/mol while the reference compound Colchicine exerted docking score of -7.046 kcal/mol. Following the analysis of MM-GBSA and ADME studies, HIT1 and HIT4 emerged as the two promising hits. To verify their thermodynamic stability at the target site, molecular dynamic simulations were carried out. Both HITs were further subjected to DFT analysis to determine their HOMO-LUMO energy gap for ensuring their biological feasibility. Finally, molecular docking based structural exploration for 1,3,4-oxadiazoles to set up a lead of Formula I for further advancements of tubulin polymerization inhibitors as anti-cancer agents.Communicated by Ramaswamy H. Sarma.

Recent Developments in Coumarin Derivatives as Neuroprotective Agents.

BACKGROUND: Neurodegenerative diseases are among the diseases that cause the foremost burden on the health system of the world. The diseases are multifaceted and difficult to treat because of their complex pathophysiology, which includes protein aggregation, neurotransmitter breakdown, metal dysregulation, oxidative stress, neuroinflammation, excitotoxicity, etc. None of the currently available therapies has been found to be significant in producing desired responses without any major side effects; besides, they only give symptomatic relief otherwise indicated off-episode relief. Targeting various pathways, namely choline esterase, monoamine oxidase B, cannabinoid system, metal chelation, -secretase, oxidative stress, etc., may lead to neurodegeneration. By substituting various functional moieties over the coumarin nucleus, researchers are trying to produce safer and more effective neuroprotective agents. OBJECTIVES: This study aimed to review the current literature to produce compounds with lower side effects using coumarin as a pharmacophore. METHODS: In this review, we have attempted to compile various synthetic strategies that have been used to produce coumarin and various substitutional strategies used to produce neuroprotective agents from the coumarin pharmacophore. Moreover, structure-activity relationships of substituting coumarin scaffold at various positions, which could be instrumental in designing new compounds, were also discussed. RESULTS: The literature review suggested that coumarins and their derivatives can act as neuroprotective agents following various mechanisms. CONCLUSION: Various studies have demonstrated the neuroprotective activity of coumarin due to an oxaheterocyclic loop, which allows binding with a broad array of proteins, thus motivating researchers to explore its potential as a lead against various neurodegenerative diseases.

Long term follow-up results of enucleation as the definitive treatment for melanocytic neuroectodermal tumour of infancy and a review on its treatment.

Introduction: Melanotic Neuroectodermal tumour of Infancy (MNTI) is a rare entity of pigmented neoplasms of head and neck region. It predominantly occurs within the first year of life. The authors present enucleation as the definitive surgical treatment, with reference to the five departmental cases of MNTI with no recurrence at 5years and 1year of follow-up of other 4 cases. Case presentation: Five cases of MNTI (age group of 2.5months-7 months) presented to our department as a large bluish-brown non tender swelling protruding into the oral cavity. Radiologic imaging revealed a well-circumscribed solid-cystic enhancing lesion causing elevation of orbit and nasal obliteration in maxillary region and causing buccolingual expansion in mandible. The tumor was enucleated without any bony margin. Histopathological and immunohistochemical evaluation (EMA, Pan Cytokeratin, HMB45, S100, p53, ki67) were done. Patients were followed up at regular intervals and had no recurrence at mean 3years follow-up. A detailed mention of surgical pearls, differential diagnosis and a brief literature review are also done. Conclusion: MNTI is a pigmented neoplasm that occurs in infants and in head and neck region mostly involves the upper alveolus and maxilla, followed by skull and mandible. Incisional biopsy is needed to confirm the tumour and rule out other malignant round cell tumours. Enucleation of the lesion is necessary without the need for any extra bony margin removal. Close long term follow up is necessary. Conservative surgical approach is usually the best first choice for MNTI treatment.

Recent Updates on Indole Derivatives as Kinase Inhibitors in the Treatment of Cancer.

Cancer is becoming a global threat as its treatment accounts for many challenges. Hence, newer inventions prioritize the requirement of developing novel anticancer agents. In this context, kinases have been exclusively investigated and developed as a promising and novel class of drug targets for anticancer regimen. Indole derivatives have been found to be most effective for targeting multiple kinases, such as PIM, CDK, TK, AKT, SRC, PI3K, PKD, GSK, etc., to inhibit cell proliferation for cancer. Recently, a group of researchers have proposed their research outcomes related to this moiety, such as Zhang et al. described some potent PI3K inhibitors by substitution at the 4th position of the indole ring. Kassis et al. enumerated several potent CDK5 inhibitors by substituting the 2nd and 6th positions of the indole ring. In the present review, we have taken the initiative to summarize structure-activity relationship (SAR) studies of indole derivatives as kinase inhibitors for the development of potential inhibitors.

Extracellular polymeric substances overproduction strategy in Ferroplasma acidiphilum growth for biooxidation of low-grade gold bearing ore: Role of monosaccharides.

The adhesion of microorganisms to surfaces and the affecting factors is important in biomining pretreatment. In this research, the novelty is focused on studying the monosaccharide's impact on the adaptability and adhesivity of Ferroplasma acidiphilum for oxidization of sulfide-bearing ore containing pyrite harboring 98 % of gold in its crystal lattice. d-sucrose increased EPS production with the highest amount of pyrite dissolution (69 %) as compared to the other types of monosaccharides (d-galactose and d-fructose). Addition of 0.8 wt% d-sucrose enhanced the production of ferric ions 65 % for the ore load of 20 wt% while for the addition of 0.4 wt%, the ferric ions concentration was maximum up to 95 %. The results indicated that the addition of both yeast extract and d-sucrose with the concentration of 0.4 wt% enhanced the EPS (Extracellular Polymeric Substances) biovolume fraction from 7.5 to 32.5 v/v %.

Effectiveness of Selective Estrogen Receptor Modulators in Breast Cancer Therapy: An Update.

BACKGROUND: Breast cancer is considered to be 2nd most common cancer subtype investigated worldwide. It is mainly prevalent in postmenopausal women. Estrogen Receptor (ER) is a primary transcription factor for the survival and growth of tumors. Around 80% BCs of all classes are ER-positive (ER+). Powerful evidence for estrogen proved to be involved in BC pathogenesis both exogenously and endogenously. It brings the concept of ER inhibitors to treat BC with distinct mechanisms into focus and ER PROTACs (Proteolysis-Targeting Chimeras), AIs (Aromatase inhibitors), SERMs (Selective estrogen receptor modulators), and SERDs (Selective estrogen receptor degrader) were developed. For over 30 years, Tamoxifen, a triphenylethylene SERM, was the drug of choice solely to treat ER+BC patients. Although several SERMs got approval by US FDA after tamoxifen, complicacies remain because of dangerous adverse effects like endometrial carcinoma, hot flashes, and VTE (Venous thromboembolism). In addition to that, drug-resistant tumors put a surging need for novel, potent candidates with no or low adverse effects for ER+ BC prevention. OBJECTIVES: This article explores the possibilities of SERMs as effective BC agents. METHODS: A detailed literature survey of the history and recent advancements of SERMs has been carried out, taking BC as the primary target. This review provides information about ER structure, signaling, pharmacological action, chemical classification with SAR analysis, and benefits and adverse effects of SERMs as potential BC agents. RESULTS: Exhaustive literature studies suggested that SERMs having an agonistic, antagonistic or mixed activity to ER could efficiently inhibit BC cell proliferation. CONCLUSION: Each chemical class of SERMs comprises some salient features and potentials, which may be further investigated to obtain novel effective SERMs in BC therapy.

Thiazole and Related Heterocyclic Systems as Anticancer Agents: A Review on Synthetic Strategies, Mechanisms of Action and SAR Studies.

BACKGROUND: Cancer is the second leading cause of death worldwide. Many anticancer drugs are commercially available, but lack of selectivity, target specificity, cytotoxicity, and development of resistance lead to serious side effects. Several experiments have been going on to develop compounds with minor or no side effects. OBJECTIVE: This review mainly emphasizes synthetic strategies, SAR studies, and mechanism of action if thiazole, benzothiazole, and imidazothiazole-containing compounds as anticancer agents. METHODS: Recent literature related to thiazole and thiazole-related derivatives endowed with encouraging anticancer potential is reviewed. This review emphasizes contemporary strategies used for the synthesis of thiazole and related derivatives, mechanistic targets, and comprehensive structural activity relationship studies to provide perspective into the rational design of high-efficiency thiazole-based anticancer drug candidates. RESULTS: Exhaustive literature survey indicated that thiazole derivatives are associated with properties of inducing apoptosis and disturbing tubulin assembly. Thiazoles are also associated with the inhibition of NFkB/mTOR/PI3K/AkT and regulation of estrogenmediated activity. Furthermore, thiazole derivatives have been found to modulate critical targets, such as topoisomerase and HDAC. CONCLUSION: Thiazole derivatives seem to be quite competent and act through various mechanisms. Some of the thiazole derivatives, such as compounds 29, 40, 62, and 74a with IC50 values of 0.05 µM, 0.00042 µM, 0.18 µM, and 0.67 µM, respectively, not only exhibit anticancer activity, but they also have lower toxicity and better absorption. Therefore, some other similar compounds could be investigated to aid in the development of anticancer pharmacophores.

Pilot Testing of the "Turbidimeter", a Simple, Universal Reader Intended to Complement and Enhance Bacterial Growth Detection in Manual Blood Culture Systems in Low-Resource Settings.

Bloodstream infections and antimicrobial resistance are an increasing problem in low-income countries. There is a clear need for adapted diagnostic tools. To address this need, we developed a simple, universal reader prototype that detects bacterial growth in blood culture bottles. Our "turbidimeter" evaluates bacterial growth, based on the turbidity of the broth and the color change of the colorimetric CO2 indicator in commercially available blood culture bottles. A total of 60 measurements were performed using 10 relevant microbial species, spiked in horse blood, to compare the turbidimeter's performance with that of an automatic reference system. The turbidimeter was able to detect growth in all but one of the spiked blood culture bottles. In the majority (7/10) of the species tested, time-to-detection of the turbidimeter was shown to be non-inferior to the reference automated time-to-detection. This was, however, only the case when both the turbidity and color change in the colorimetric CO2-indicator were used to evaluate growth. We could not demonstrate the non-inferiority of the turbidity measurement alone. Overall, the turbidimeter performed well, but we also identified some improvements that will be implemented in the next version of the prototype.

Recent Developments in Oxazole Derivatives as Anticancer Agents: Review on Synthetic Strategies, Mechanism of Action and SAR Studies.

BACKGROUND: Cancer is the world's third deadliest disease. Despite the availability of numerous treatments, researchers are focusing on the development of new drugs with no resistance and toxicity issues. Many newly synthesized drugs fail to reach clinical trials due to poor pharmacokinetic properties. Therefore, there is an imperative requisite to expand novel anticancer agents with in vivo efficacy. OBJECTIVE: This review emphasizes synthetic methods, contemporary strategies used for the inclusion of oxazole moiety, mechanistic targets, along with comprehensive structure-activity relationship studies to provide perspective into the rational design of highly efficient oxazole-based anticancer drugs. METHODS: Literature related to oxazole derivatives engaged in cancer research is reviewed. This article gives a detailed account of synthetic strategies, targets of oxazole in cancer, including STAT3, Microtubules, G-quadruplex, DNA topoisomerases, DNA damage, protein kinases, miscellaneous targets, in vitro studies, and some SAR studies. RESULTS: Oxazole derivatives possess potent anticancer activity by inhibiting novel targets such as STAT3 and Gquadruplex. Oxazoles also inhibit tubulin protein to induce apoptosis in cancer cells. Some other targets such as DNA topoisomerase enzyme, protein kinases, and miscellaneous targets including Cdc25, mitochondrial enzymes, HDAC, LSD1, HPV E2 TAD, NQO1, Aromatase, BCl-6, Estrogen receptor, GRP-78, and Keap-Nrf2 pathway are inhibited by oxazole derivatives. Many derivatives showed excellent potencies on various cancer cell lines with IC50 values in nanomolar concentrations. CONCLUSION: Oxazole is a five-membered heterocycle, with oxygen and nitrogen at 1 and 3 positions, respectively. It is often combined with other pharmacophores in the expansion of novel anticancer drugs. In summary, oxazole is a promising entity to develop new anticancer drugs.

Structural Aspects of mTOR Inhibitors: Search for Potential Compounds.

mTOR (mammalian target of rapamycin) is a catalytic subunit composed of two multi-protein complexes that indicate mTORC1 and mTORC2. It plays a crucial role in various fundamental cell processes like cell proliferation, metabolism, survival, cell growth, etc. Various first line mTOR inhibitors such as Rapamycin, Temsirolimus, Everolimus, Ridaforolimus, Umirolimus, and Zotarolimus have been used popularly. In contrast, several mTOR inhibitors such as Gedatolisib (PF-05212384) are under phase 2 clinical trials studies for the treatment of triple-negative breast cancer. The mTOR inhibitors bearing heterocyclic moieties such as quinazoline, thiophene, morpholine, imidazole, pyrazine, furan, quinoline are under investigation against various cancer cell lines (U87MG, PC-3, MCF-7, A549, MDA-231). In this review, we summarized updated research related to mTOR inhibitors and their structure-activity relationship, which may help scientists develop potent inhibitors against cancer.

Growth Outcome and Jaw Functions Are Better After Gap Arthroplasty Plus Costochondral Graft Reconstruction Than Gap Arthroplasty Alone in Pediatric Temporomandibular Joint Ankylosis Patients: A Cluster Randomized Controlled Trial.

PURPOSE: It is not known if the muscle matrix that becomes functional after gap arthroplasty (GA) in temporomandibular joint ankylosis (TMJA), induces growth of the mandible or the reconstructive arthroplasty with costochondral graft (CCG) is responsible for growth. The study aimed to evaluate the mandibular growth and functional outcome with the use of CCG/GA in the management of pediatric TMJA. METHODS: The investigators designed a cluster randomized controlled trial on pediatric (3 to 16 years) TMJA patients. Treatment applied (CCG and GA), was the primary predictor variable. Patients were divided into CCG and GA groups. The primary outcome variable was growth. Secondary outcome variables included etiology and duration of ankylosis, maximal incisal opening (MIO), reankylosis, occlusion, laterotrusion, chin deviation, facial asymmetry, occlusal tilt, and complications. The distance condylion (Co) to gnathion (Gn) was used to measure mandibular length. Ramal height was measured from Co- gonion (Go). Lower facial height was measured from the anterior nasal spine to Gn. Generalized estimating equations were used to calculate the regression coefficient adjusted for the cluster. The patient was considered as a cluster and the unit of analysis was joint. RESULTS: Fifty-six {n = 28 in each group, (n = 33 joint in the CCG group and n = 31 joints in GA group)} patients were analyzed. The median follow-up was 33-months (31.93 ± 15.24) in the CCG group and 32-months (32.85 ± 17.84) in the GA group. Intergroup comparison between the CCG and GA group showed a statistically significant difference in mandibular length (CCG = 77.51 ± 9.31 and GA = 66.66 ± 8.32 mm, P < .001), ramal height (CCG = 44.21 ± 7.3 and GA = 31.87 ± 8.4 mm, P < .001), and statistically insignificant difference in lower facial height (CCG = 52.53 ± 6.1 and GA = 50.19 ± 6.3 mm, P = 0.14) at follow-up. Statistically, significant improvement was seen in MIO in both groups (<.001). CONCLUSIONS: The results of the present study concluded that growth and jaw functions were better in reconstructive arthroplasty with CCG than GA in pediatric TMJA.

Does no-intraoperative correction of chin deviation prevent costochondral graft overgrowth in pediatric temporomandibular joint ankylosis management - an intermediate outcome study.

The use of costochondral graft is controversial for pediatric temporomandibular joint reconstruction due to its unpredictable growth. The height of the cartilage is directly responsible for the growth capacity of costochondral graft. Even after keeping the cartilage in costochondral graft to a recommended height, overgrowth has been reported. Traditionally during costochondral graft fixation, chin deviation is corrected intraoperatively. The investigators hypothesized that this intraoperative manipulation of mandible to correct chin deviation and maintaining the chin in new position causes excessive stress and strain in the muscular functional matrix. The authors believe that this may be the reason for excessive growth trigger on the grafted side. This study intends to prove the hypothesis of no-intraoperative correction of chin deviation can prevent overgrowth of the costochondral graft. We implied this technique in pediatric temporomandibular joint ankylosis patients managed with osteoarthrectomy and reconstructed with costochondral graft. Patients with at least a follow-up of 30-months were included in the study. The study sample consisted of 20 patients. All the patients had adequate growth with improvement in facial asymmetry. The results of the present study supports our hypothesis of no-intraoperative correction of chin deviation as a technique to prevent overgrowth of costochondral graft. We recommend this technique to allow catch-up of growth rather than acceleration of growth. This change in technique needs more research, randomized controlled trial for reliability and long-term results.

Pyrazolopyrimidines as anticancer agents: A review on structural and target-based approaches.

Pyrazolopyrimidine scaffold is one of the privileged heterocycles in drug discovery. This scaffold produced numerous biological activities in which anticancer is important one. Previous studies showed its importance in interactions with various receptors such as growth factor receptor, TGFBR2 gene, CDK2/cyclin E and Abl kinase, adenosine receptor, calcium-dependent Protein Kinase, Pim-1 kinase, Potent Janus kinase 2, BTK kinase, P21-activated kinase 1, extracellular signal-regulated kinase 2, histone lysine demethylase and Human Kinesin-5. However, there is a need of numerous studies for the discovery of target based potential compounds. The structure activity relationship studies may help to explore the generation of potential compounds in short time period. Therefore, in the present review we tried to explore the structural aspects of Pyrazolopyrimidine with their structure activity relationship against various targets for the development of potential compounds. The current review is the compilation of significant advances made on Pyrazolopyrimidines reported between 2015 and 2020.

Isoxazole derivatives as anticancer agent: A review on synthetic strategies, mechanism of action and SAR studies.

Breast cancer is the second most leading cause of death among women. Multiple drugs have been approved by FDA for the treatment of BC. The major drawbacks of existing drugs are the development of resistance, toxicity, selectivity problem. The other therapies like hormonal therapy, surgery, radiotherapy, and immune therapy are in use but showed many side effects like bioavailability issues, non-selectivity, pharmacokinetic-pharmacodynamic problems. Therefore, there is an urgent need to develop new moieties that are nonviolent and more effective in the treatment of cancer. Isoxazole derivatives have gain popularity in recent years due to anticancer potential with the least side effects. These derivatives act as an anticancer agent with different mechanisms like inducing apoptosis, aromatase inhibition, disturbing tubulin congregation, topoisomerase inhibition, HDAC inhibition, and ERα inhibition. In this article, we have explored the synthetic strategies, anticancer mechanism of action along with SAR studies of isoxazole derivatives.