cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.27604812
title: Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives

description: Transcriptional enhanced associate domain (TEAD) transcription factors undergo auto-palmitoylation, which is critical to mediate their function and maintain stability. Targeting the palmitate binding pocket of TEAD holds considerable promise for drug discovery, and it can be characterised into three components: a conserved cysteine, a hydrophobic main pocket, and a hydrophilic side pocket. Endogenous palmitate and several known TEAD inhibitors interact with the cysteine and hydrophobic residues in the deep hydrophobic pocket. We anticipate that precise targeting of the polar side pocket could facilitate the discovery of inhibitors with enhanced potencies and properties. Herein, we selected niflumic acid as the core scaffold suitable for targeting the three characteristic components of TEAD palmitate pocket. Reversible and irreversible compounds with substituents capable of directing each part of the palmitate pocket were designed. The newly synthesised compounds inhibited the palmitoylation and transcriptional activity of TEAD and elicited growth-inhibitory effects against several carcinomas, including mesothelioma.
DOI: 10.6084/m9.figshare.26661555
title: Non-small cell lung cancer sensitisation to platinum chemotherapy via new thiazole-triazole hybrids acting as dual T-type CCB/MMP-9 inhibitors

description: Cisplatin remains the unchallenged standard therapy for NSCLC. However, it is not completely curative due to drug resistance and oxidative stress-induced toxicity. Drug resistance is linked to overexpression of matrix metalloproteinases (MMPs) and aberrant calcium signalling. We report synthesis of novel thiazole-triazole hybrids as MMP-9 inhibitors with T-type calcium channel blocking and antioxidant effects to sensitise NSCLC to cisplatin and ameliorate its toxicity. MTT and whole cell patch clamp assays revealed that <b>6d</b> has a balanced profile of cytotoxicity (IC<sub>50</sub> = 21 ± 1 nM, SI = 12.14) and T-type calcium channel blocking activity (⁓60% at 10 μM). It exhibited moderate ROS scavenging activity and nanomolar MMP-9 inhibition (IC<sub>50</sub> = 90 ± 7 nM) surpassing NNGH with MMP-9 over −2 and MMP-10 over −13 selectivity. Docking and MDs simulated its receptor binding mode. Combination studies confirmed that <b>6d</b> synergized with cisplatin (CI = 0.69 ± 0.05) lowering its IC<sub>50</sub> by 6.89 folds. Overall, the study introduces potential lead adjuvants for NSCLC platinum-based therapy.
DOI: 10.6084/m9.figshare.26661555.v1
title: Non-small cell lung cancer sensitisation to platinum chemotherapy via new thiazole-triazole hybrids acting as dual T-type CCB/MMP-9 inhibitors

description: Cisplatin remains the unchallenged standard therapy for NSCLC. However, it is not completely curative due to drug resistance and oxidative stress-induced toxicity. Drug resistance is linked to overexpression of matrix metalloproteinases (MMPs) and aberrant calcium signalling. We report synthesis of novel thiazole-triazole hybrids as MMP-9 inhibitors with T-type calcium channel blocking and antioxidant effects to sensitise NSCLC to cisplatin and ameliorate its toxicity. MTT and whole cell patch clamp assays revealed that <b>6d</b> has a balanced profile of cytotoxicity (IC<sub>50</sub> = 21 ± 1 nM, SI = 12.14) and T-type calcium channel blocking activity (⁓60% at 10 μM). It exhibited moderate ROS scavenging activity and nanomolar MMP-9 inhibition (IC<sub>50</sub> = 90 ± 7 nM) surpassing NNGH with MMP-9 over −2 and MMP-10 over −13 selectivity. Docking and MDs simulated its receptor binding mode. Combination studies confirmed that <b>6d</b> synergized with cisplatin (CI = 0.69 ± 0.05) lowering its IC<sub>50</sub> by 6.89 folds. Overall, the study introduces potential lead adjuvants for NSCLC platinum-based therapy.
DOI: 10.6084/m9.figshare.27604812.v1
title: Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives

description: Transcriptional enhanced associate domain (TEAD) transcription factors undergo auto-palmitoylation, which is critical to mediate their function and maintain stability. Targeting the palmitate binding pocket of TEAD holds considerable promise for drug discovery, and it can be characterised into three components: a conserved cysteine, a hydrophobic main pocket, and a hydrophilic side pocket. Endogenous palmitate and several known TEAD inhibitors interact with the cysteine and hydrophobic residues in the deep hydrophobic pocket. We anticipate that precise targeting of the polar side pocket could facilitate the discovery of inhibitors with enhanced potencies and properties. Herein, we selected niflumic acid as the core scaffold suitable for targeting the three characteristic components of TEAD palmitate pocket. Reversible and irreversible compounds with substituents capable of directing each part of the palmitate pocket were designed. The newly synthesised compounds inhibited the palmitoylation and transcriptional activity of TEAD and elicited growth-inhibitory effects against several carcinomas, including mesothelioma.
DOI: 10.6084/m9.figshare.27232654
title: Design, synthesis and biological evaluation of marine naphthoquinone-naphthol derivatives as potential anticancer agents

description: 1’-Hydroxy-4’,8,8’-trimethoxy-[2,2’-binaphthalene]-1,4-dione (compound <b>5</b>), a secondary metabolite recently discovered in marine fungi, demonstrates promising cytotoxic and anticancer potential. However, knowledge regarding the anticancer activities and biological mechanisms of its derivatives remains limited. Herein, a series of novel naphthoquinone-naphthol derivatives were designed, synthesised, and evaluated for their anticancer activity against cancer cells of different origins. Among these, Compound <b>13</b>, featuring an oxopropyl group at the <i>ortho</i>-position of quinone group, exhibited the most potent inhibitory effects on HCT116, PC9, and A549 cells, with IC<sub>50</sub> values decreasing from 5.27 to 1.18 μM (4.5-fold increase), 6.98 to 0.57 μM (12-fold increase), and 5.88 to 2.25 μM (2.6-fold increase), respectively, compared to compound <b>5</b>. Further mechanistic studies revealed that compound <b>13</b> significantly induced cell apoptosis by increasing the expression levels of cleaved caspase-3 and reducing Bcl-2 proteins through downregulating the EGFR/PI3K/Akt signalling pathway, leading to the inhibition of proliferation in HCT116 and PC9 cells. The present findings suggest this novel naphthoquinone-naphthol derivative may hold potential as an anticancer therapeutic lead.
DOI: 10.6084/m9.figshare.27232654.v1
title: Design, synthesis and biological evaluation of marine naphthoquinone-naphthol derivatives as potential anticancer agents

description: 1’-Hydroxy-4’,8,8’-trimethoxy-[2,2’-binaphthalene]-1,4-dione (compound <b>5</b>), a secondary metabolite recently discovered in marine fungi, demonstrates promising cytotoxic and anticancer potential. However, knowledge regarding the anticancer activities and biological mechanisms of its derivatives remains limited. Herein, a series of novel naphthoquinone-naphthol derivatives were designed, synthesised, and evaluated for their anticancer activity against cancer cells of different origins. Among these, Compound <b>13</b>, featuring an oxopropyl group at the <i>ortho</i>-position of quinone group, exhibited the most potent inhibitory effects on HCT116, PC9, and A549 cells, with IC<sub>50</sub> values decreasing from 5.27 to 1.18 μM (4.5-fold increase), 6.98 to 0.57 μM (12-fold increase), and 5.88 to 2.25 μM (2.6-fold increase), respectively, compared to compound <b>5</b>. Further mechanistic studies revealed that compound <b>13</b> significantly induced cell apoptosis by increasing the expression levels of cleaved caspase-3 and reducing Bcl-2 proteins through downregulating the EGFR/PI3K/Akt signalling pathway, leading to the inhibition of proliferation in HCT116 and PC9 cells. The present findings suggest this novel naphthoquinone-naphthol derivative may hold potential as an anticancer therapeutic lead.
DOI: 10.6084/m9.figshare.27636567
title: Structure optimization and molecular dynamics studies of new tumor-selective <i>s</i>-triazines targeting DNA and MMP-10/13 for halting colorectal and secondary liver cancers

description: A series of triazole-tethered triazines bearing pharmacophoric features of DNA-targeting agents and non-hydroxamate MMPs inhibitors were synthesized and screened against HCT-116, Caco-2 cells, and normal colonocytes by MTT assay. <b>7a</b> and <b>7g</b> surpassed doxorubicin against HCT-116 cells regarding potency (IC<sub>50</sub> = 0.87 and 1.41 nM) and safety (SI = 181.93 and 54.41). <b>7g</b> was potent against liver cancer (HepG-2; IC<sub>50</sub> = 65.08 nM), the main metastatic site of CRC with correlation to MMP-13 expression. Both derivatives induced DNA damage at 2.67 and 1.87 nM, disrupted HCT-116 cell cycle and triggered apoptosis by 33.17% compared to doxorubicin (DNA damage at 0.76 nM and 40.21% apoptosis induction). <b>7g</b> surpassed NNGH against MMP-10 (IC<sub>50</sub> = 0.205 μM) and MMP-13 (IC<sub>50</sub> = 0.275 μM) and downregulated HCT-116 VEGF related to CRC progression by 38%. Docking and MDs simulated ligands-receptors binding modes and highlighted SAR. Their ADMET profiles, drug-likeness and possible off-targets were computationally predicted.
DOI: 10.6084/m9.figshare.27636567.v1
title: Structure optimization and molecular dynamics studies of new tumor-selective <i>s</i>-triazines targeting DNA and MMP-10/13 for halting colorectal and secondary liver cancers

description: A series of triazole-tethered triazines bearing pharmacophoric features of DNA-targeting agents and non-hydroxamate MMPs inhibitors were synthesized and screened against HCT-116, Caco-2 cells, and normal colonocytes by MTT assay. <b>7a</b> and <b>7g</b> surpassed doxorubicin against HCT-116 cells regarding potency (IC<sub>50</sub> = 0.87 and 1.41 nM) and safety (SI = 181.93 and 54.41). <b>7g</b> was potent against liver cancer (HepG-2; IC<sub>50</sub> = 65.08 nM), the main metastatic site of CRC with correlation to MMP-13 expression. Both derivatives induced DNA damage at 2.67 and 1.87 nM, disrupted HCT-116 cell cycle and triggered apoptosis by 33.17% compared to doxorubicin (DNA damage at 0.76 nM and 40.21% apoptosis induction). <b>7g</b> surpassed NNGH against MMP-10 (IC<sub>50</sub> = 0.205 μM) and MMP-13 (IC<sub>50</sub> = 0.275 μM) and downregulated HCT-116 VEGF related to CRC progression by 38%. Docking and MDs simulated ligands-receptors binding modes and highlighted SAR. Their ADMET profiles, drug-likeness and possible off-targets were computationally predicted.
DOI: 10.15468/dl.h7mkrk
title: Occurrence Download

description: A dataset containing 180727 species occurrences available in GBIF matching the query:
{
 "DatasetKey" : [
 "is Lund University Biological Museum - Insect collections Inventory"
 ]
}

 The dataset includes 180727 records from 1 constituent datasets; see https://api.gbif.org/v1/occurrence/download/0049095-241126133413365/datasets/export for details.
 
Data from some individual datasets included in this download may be licensed under less restrictive terms.
DOI: 10.6084/m9.figshare.27853982
title: Discovery of novel 2,4-diarylaminopyrimidine hydrazone derivatives as potent anti-thyroid cancer agents capable of inhibiting FAK

description: In this work, thirty 2,4-diarylaminopyrimidine-based hydrazones were designed, synthesised, and their anti-thyroid cancer activity were explored. The majority of compounds exhibit moderate to excellent cytotoxic activity against FAK overexpressing TPC-1 cells, with IC<sub>50</sub> values ranging from 0.113 to 1.460 μM. Among them, compound <b>14f</b> displayed exceptional anti-proliferative effect against TPC-1 cells (IC<sub>50</sub> = 0.113 μM) and potent FAK inhibitory potency (IC<sub>50</sub> = 35 nM). In <i>silico</i> studies indicated that compound <b>14f</b> could well bind to FAK (Focal Adhesion Kinase) and have favourable pharmacokinetic profiles. In addition, compound <b>14f</b> could inhibit the phosphorylation of FAK at Tyr397, Tyr576/577 and Tyr925, and did not affect the expression level of FAK in TPC-1 cells. Compound <b>14f</b> was also effective in inhibiting the proliferation and migration of thyroid cancer cells TPC-1. Thus, these novel 4-arylaminopyrimidine hydrazone derivatives exhibited potent anti-thyroid cancer activities through the inhibition of FAK.
DOI: 10.6084/m9.figshare.27853982.v1
title: Discovery of novel 2,4-diarylaminopyrimidine hydrazone derivatives as potent anti-thyroid cancer agents capable of inhibiting FAK

description: In this work, thirty 2,4-diarylaminopyrimidine-based hydrazones were designed, synthesised, and their anti-thyroid cancer activity were explored. The majority of compounds exhibit moderate to excellent cytotoxic activity against FAK overexpressing TPC-1 cells, with IC<sub>50</sub> values ranging from 0.113 to 1.460 μM. Among them, compound <b>14f</b> displayed exceptional anti-proliferative effect against TPC-1 cells (IC<sub>50</sub> = 0.113 μM) and potent FAK inhibitory potency (IC<sub>50</sub> = 35 nM). In <i>silico</i> studies indicated that compound <b>14f</b> could well bind to FAK (Focal Adhesion Kinase) and have favourable pharmacokinetic profiles. In addition, compound <b>14f</b> could inhibit the phosphorylation of FAK at Tyr397, Tyr576/577 and Tyr925, and did not affect the expression level of FAK in TPC-1 cells. Compound <b>14f</b> was also effective in inhibiting the proliferation and migration of thyroid cancer cells TPC-1. Thus, these novel 4-arylaminopyrimidine hydrazone derivatives exhibited potent anti-thyroid cancer activities through the inhibition of FAK.
DOI: 10.6084/m9.figshare.27095895
title: Synthesis and biological evaluation of <i>ortho</i>-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases

description: Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid <b>LH4f</b> as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound’s selectivity towards class IIa HDACs, the <i>ortho</i>-phenyl group from the selective HDAC7 inhibitor <b>1</b> is incorporated into <i>ortho</i> position of the phenylhydroxamic acid in <b>LH4f</b>. Compared to <b>LH4f</b>, most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound <b>7 g</b> exhibited the strongest HDAC9 inhibition with an IC<sub>50</sub> value of 40 nM. Molecular modelling further identified the key interactions of compound <b>7 g</b> bound to HDAC9. Compound <b>7 g</b> significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics.
DOI: 10.6084/m9.figshare.27095895.v1
title: Synthesis and biological evaluation of <i>ortho</i>-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases

description: Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid <b>LH4f</b> as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound’s selectivity towards class IIa HDACs, the <i>ortho</i>-phenyl group from the selective HDAC7 inhibitor <b>1</b> is incorporated into <i>ortho</i> position of the phenylhydroxamic acid in <b>LH4f</b>. Compared to <b>LH4f</b>, most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound <b>7 g</b> exhibited the strongest HDAC9 inhibition with an IC<sub>50</sub> value of 40 nM. Molecular modelling further identified the key interactions of compound <b>7 g</b> bound to HDAC9. Compound <b>7 g</b> significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics.
DOI: 10.6084/m9.figshare.27088567
title: Synthesis, molecular modelling, and biological evaluation of novel quinoxaline derivatives for treating type II diabetes

description: Quinoxalines are benzopyrazine derivatives with significant therapeutic impact in the pharmaceutical industry. They proved to be useful against inflammation, bacterial, fungal, viral infection, diabetes and other applications. Very recently, in January 2024, the FDA approved new quinoxaline containing drug, erdafitinib for treatment of certain carcinomas. Despite the diverse biological activities exhibited by quinoxaline derivatives and the role of secretory phospholipase A2 (sPLA2) in diabetes-related complications, the potential of sPLA2-targeting quinoxaline-based inhibitors to effectively address these complications remains unexplored. Therefore, we designed novel sPLA2- and α-glucosidase-targeting quinoxaline-based heterocyclic inhibitors to regulate elevated post-prandial blood glucose linked to patients with diabetes-related cardiovascular complications. Compounds <b>5a–d</b> and <b>6a–d</b> were synthesised by condensing quinoxaline hydrazides with various aryl sulphonyl chlorides. Biological screening revealed compound <b>6a</b> as a potent sPLA2 inhibitor (IC<sub>50</sub> = 0.0475 µM), whereas compound <b>6c</b> most effectively inhibited α-glucosidase (IC<sub>50</sub> = 0.0953 µM), outperforming the positive control acarbose. Moreover, compound <b>6a</b> was the best inhibitor for both enzymes. Molecular docking revealed pharmacophoric features, highlighting the importance of a sulfonohydrazide moiety in the structural design of these compounds, leading to the development of potent sPLA2 and α-glucosidase inhibitors. Collectively, our findings helped identify promising candidates for developing novel therapeutic agents for treating diabetes mellitus. A small, focused library comprising 8 novel compounds was synthesised using a series of substituted quinoxaline sulfonohydrazide derivatives.All synthesised compounds were tested against phospholipase A2 (sPLA2) and α-glucosidase enzymes.The compounds exhibited activities against α-glucosidase and were potent at nanomolar concentrations against sPLA2 isozymes.Structure-based molecular modelling was employed to rationalise the SAR of the compounds. A small, focused library comprising 8 novel compounds was synthesised using a series of substituted quinoxaline sulfonohydrazide derivatives. All synthesised compounds were tested against phospholipase A2 (sPLA2) and α-glucosidase enzymes. The compounds exhibited activities against α-glucosidase and were potent at nanomolar concentrations against sPLA2 isozymes. Structure-based molecular modelling was employed to rationalise the SAR of the compounds.
DOI: 10.6084/m9.figshare.27088567.v1
title: Synthesis, molecular modelling, and biological evaluation of novel quinoxaline derivatives for treating type II diabetes

description: Quinoxalines are benzopyrazine derivatives with significant therapeutic impact in the pharmaceutical industry. They proved to be useful against inflammation, bacterial, fungal, viral infection, diabetes and other applications. Very recently, in January 2024, the FDA approved new quinoxaline containing drug, erdafitinib for treatment of certain carcinomas. Despite the diverse biological activities exhibited by quinoxaline derivatives and the role of secretory phospholipase A2 (sPLA2) in diabetes-related complications, the potential of sPLA2-targeting quinoxaline-based inhibitors to effectively address these complications remains unexplored. Therefore, we designed novel sPLA2- and α-glucosidase-targeting quinoxaline-based heterocyclic inhibitors to regulate elevated post-prandial blood glucose linked to patients with diabetes-related cardiovascular complications. Compounds <b>5a–d</b> and <b>6a–d</b> were synthesised by condensing quinoxaline hydrazides with various aryl sulphonyl chlorides. Biological screening revealed compound <b>6a</b> as a potent sPLA2 inhibitor (IC<sub>50</sub> = 0.0475 µM), whereas compound <b>6c</b> most effectively inhibited α-glucosidase (IC<sub>50</sub> = 0.0953 µM), outperforming the positive control acarbose. Moreover, compound <b>6a</b> was the best inhibitor for both enzymes. Molecular docking revealed pharmacophoric features, highlighting the importance of a sulfonohydrazide moiety in the structural design of these compounds, leading to the development of potent sPLA2 and α-glucosidase inhibitors. Collectively, our findings helped identify promising candidates for developing novel therapeutic agents for treating diabetes mellitus. A small, focused library comprising 8 novel compounds was synthesised using a series of substituted quinoxaline sulfonohydrazide derivatives.All synthesised compounds were tested against phospholipase A2 (sPLA2) and α-glucosidase enzymes.The compounds exhibited activities against α-glucosidase and were potent at nanomolar concentrations against sPLA2 isozymes.Structure-based molecular modelling was employed to rationalise the SAR of the compounds. A small, focused library comprising 8 novel compounds was synthesised using a series of substituted quinoxaline sulfonohydrazide derivatives. All synthesised compounds were tested against phospholipase A2 (sPLA2) and α-glucosidase enzymes. The compounds exhibited activities against α-glucosidase and were potent at nanomolar concentrations against sPLA2 isozymes. Structure-based molecular modelling was employed to rationalise the SAR of the compounds.
DOI: 10.6084/m9.figshare.25416333
title: Elucidation of critical chemical moieties of metallo-β-lactamase inhibitors and prioritisation of target metallo-β-lactamases

description: The urgent demand for effective countermeasures against metallo-β-lactamases (MBLs) necessitates development of novel metallo-β-lactamase inhibitors (MBLIs). This study is dedicated to identifying critical chemical moieties within previously developed MBLIs, and critical MBLs should serve as the target in MBLI evaluations. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), a systematic literature analysis was conducted, and the NCBI RefSeq genome database was exploited to access the abundance profile and taxonomic distribution of MBLs and their variant types. Through the implementation of two distinct systematic approaches, we elucidated critical chemical moieties of MBLIs, providing pivotal information for rational drug design. We also prioritised MBLs and their variant types, highlighting the imperative need for comprehensive testing to ensure the potency and efficacy of the newly developed MBLIs. This approach contributes valuable information to advance the field of antimicrobial drug discovery.