Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors

Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (TOP2) mediated DNA damages and causes cellular resistance to clinically used TOP2 poisons. Inhibiting TDP2 can potentially sensitize cancer cells toward TOP2 poisons. Commercial compound P10A10, to which the structure was assigned as 7-phenyl triazolopyrimidine analogue 6a, was previously identified as a TDP2 inhibitor hit in our virtual and fluorescence-based biochemical screening campaign. We report herein that the hit validation through resynthesis and structure elucidation revealed the correct structure of P10A10 (Chembridge ID 7236827) to be the 5-phenyl triazolopyrimidine regioisomer 7a. Subsequent structure–activity relationship (SAR) via the synthesis of a total of 47 analogues of both the 5-phenyl triazolopyrimidine scaffold (7) and its bioisosteric triazolopyridine scaffold (17) identified four derivatives (7a, 17a, 17e, and 17z) with significant TDP2 inhibition (IC₅₀?<?50?µM), with 17z showing excellent cell permeability and no cytotoxicity.     

Cytotoxic and anti-inflammatory salicin glycosides from leaves of Salix acmophylla

The species of genus Salix, commonly known as Willow, are well known worldwide as rich source of medicinally important salicin derivatives and phenolic glycosides. The current study focuses on Salix acmophylla Bioss with the aim of identifying new bioactive constituents of this plant. Two new salicin glycosides, acmophyllin A (1), acmophyllin B (2) and five reported phenolic glycosides 3⿿7, were identified from S. acmophylla Bioss. NMR and mass spectroscopic techniques were employed to elucidate the structure of secondary metabolites of S. acmophylla. The new salicin glycosides were evaluated against three different cancer cell lines i.e., PSN-1 (pancreatic cancer cells), MCF-7 (breast cancer cells) and NCI-H460 (lung cancer cells). The acmophyllin A (1) exhibited cytotoxicity in a dose dependent manner against all three cancer cells (IC₅₀ ⿼35⿿40 μM). Acmophyllin B (2) exhibited mild activity against PSN-1 cells and MCF-7 cancer cells. In addition, compounds 5 and 6 showed potent inhibition of oxidative burst in zymosan activated neutrophils by chemiluminescence technique, while no other compound were found to inhibit the production of reactive oxygen species (ROS).     

Identification of novel inhibitors for the tyrosyl-DNA-phosphodiesterase 1 (Tdp1) mutant SCAN1 using virtual screening

Spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1) is a debilitating neurological disease that is caused by the mutation the Tyrosyl-DNA phosphodiesterase 1 (TDP1) DNA repair enzyme. The crucial His493 in TDP1′s binding site is replaced with an arginine amino acid residue rendering the enzyme dysfunctional. A virtual screen was performed against the homology model of SCAN1 and seventeen compounds were identified and tested in a novel SCAN1 specific biochemical assay. Six compounds showed activity with IC₅₀ values between 3.5 and 25.1 µM. The most active ligand 5 (3.5 µM) is a dicoumarin followed by a close structural analogue 6 at 6.0 µM. A less potent series of β-carbolines (14 and 15) was found with potency in the mid-teens. According to molecular modelling an excellent fit for the active ligands into the binding pocket is predicted. To the best of our knowledge, data on inhibitors of the mutant form of TDP1 has not been reported previously. The virtual hits were also tested for wild type TDP1 activity and all six SCAN1 inhibitors are potent for the former, e.g., ligand 5 has a measured IC₅₀ at 99 nM.In the last decade, TDP1 is considered as a promising target for adjuvant therapy against cancer in combination with Topoisomerase 1 poisons. The active ligands are mostly non-toxic to cancer cell lines A-549, T98G and MCF-7 as well as the immortalized WI-38 human fetal lung cells. Furthermore, ligands 5 and 7, show promising synergy in conjunction with topotecan, a clinically used topoisomerase 1 anticancer drug. The active ligands 5, 7, 14 and 15 have a good balance of the physicochemical properties required for oral bioavailability making the excellent candidates for further development.     

Design and molecular modeling of novel P38α MAPK inhibitors targeting breast cancer,synthesized from oxygen heterocyclic natural compounds

Two new series of furochromone and benzofuran derivatives were designed, synthesized and evaluated for their in vitro anticancer activity against MCF-7 and MDA231 breast cancer cell lines. Compounds 5, 6, 7, 9, 15a, 16, 17a and 18 exhibited the best antiproliferative activities with IC₅₀ values ranging from 1.19 to 2.78?µM against MCF-7 superior to lapatinib as reference standard (IC₅₀; 4.69?µM). Compounds 15a and 18 revealed significant cytotoxic activity against MCF-7 and MDA231, therefore their inhibitory potencies against p38α MAP kinase were evaluated. Remarkably they exhibited significant IC₅₀ of 0.04?µM comparable to SB203580 (IC₅₀; 0.50?µM) as a reference standard. These promising results of cytotoxic activity and significant inhibition of p38α MAP kinase, were confirmed by exploring the effect of benzofuran derivative (18) on the apoptotic induction and cell cycle progression of MCF-7 cell line. Compound 18 induced preG1 apoptosis and cell growth arrest at G2/M phase preventing the mitotic cycle. Moreover it activated the caspase-7 which executes apoptosis. Molecular docking study was carried out using GOLD program to predict the mode of binding interaction of the synthesized compounds into the target p38α MAPK. Additionally, the physicochemical properties and ADME parameters of compound 18 were examined in silico to investigate its drug-likeness.     

Cytotoxic triterpene saponins from the stem bark of Kalopanax pictus

Three new compounds, 3β,6β,23-trihydroxyolean-12-en-28-oic acid 3-O-α-l-arabinopyranoside (1), kalopanaxsaponin L (2), and kalopanaxsaponin M (13), as well as eleven known compounds (3–12 and 14), were isolated from the stem bark of Kalopanax pictus. Their structures were determined on the basis of extentive spectroscopic analyses and acid hydrolysis. The cytotoxicity of the compounds was evaluated in three human carcinoma cell lines, including HL-60, HCT-116, and MCF-7. Compounds 1, 5–8, 10, and 11 exhibited significantly cytotoxic activity toward HL-60 cells, with IC₅₀ values ranging from 0.1 to 6.9 μM. Compounds 4–7 and 14 showed significant cytotoxicity against HCT-116 cells, with IC₅₀ values ranging from 0.4 to 9.2 μM. Remarkably, the cytotoxic activities of compounds 5–7 against HCT-116 cells were greater than that of the anticancer chemotherapy drug, mitoxantrone (IC₅₀ = 3.7 μM). Compounds 1, 3, 5, and 14 were cytotoxic toward MCF-7 cells with IC₅₀ values in a range of 7.4–14.5 μM.     

Synthesis,biological evaluation and docking study of a new series of di-substituted benzoxazole derivatives as selective COX-2 inhibitors and anti-inflammatory agents

A new series of substituted-N-(3,4-dimethoxyphenyl)-benzoxazole derivatives 13a–13p was synthesized and evaluated in vitro for their COX (I and II) inhibitory activity, in vivo anti-inflammatory and ulcerogenic potential. Compounds 13d, 13h, 13k, 13l and 13n exhibited significant COX-2 inhibitory activity and selectivity towards COX-2 over COX-1. These selected compounds were screened for their in vivo anti-inflammatory activity by carrageenan induced rat paw edema method. Among these compounds, 13d was the most promising analogs of the series with percent inhibition of 84.09 and IC₅₀ value of 0.04?µM and 1.02?µM (COX-2 and COX-1) respectively. Furthermore, ulcerogenic study was performed and tested compounds (13d, 13h, 13k, 13l) demonstrated a significant gastric tolerance than ibuprofen. Molecular docking study was also performed with resolved crystal structure of COX-2 to understand the binding mechanisms of newly synthesized inhibitors in the active site of COX-2 enzyme and the results were found to be concordant with the biological evaluation studies of the compounds. These newly synthesized inhibitors also showed acceptable pharmacokinetic profile in the in silico ADME/T analyses.     

Design,synthesis and anticancer evaluation of thieno[2,3-d]pyrimidine derivatives as dual EGFR/HER2 inhibitors and apoptosis inducers

Deregulation of many kinases is directly linked to cancer development and the tyrosine kinase family is one of the most important targets in current cancer therapy regimens. In this study, we have designed and synthesized a series of thieno[2,3-d]pyrimidine derivatives as an EGFR and HER2 tyrosine kinase inhibitors. All the synthesized compounds were evaluated in vitro for their inhibitory activities against EGFR^WT; and the most active compounds that showed promising IC₅₀ values against EGFR^WT were tested in vitro for their inhibitory activities against mutant EGFR^T790M and HER2 kinases. Moreover, the antitumor activities of these compounds were tested against four cancer cell lines (HepG2, HCT-116, MCF-7 and A431). Compounds 13g, 13h and 13k exhibited the highest activities against the examined cell lines with IC₅₀ values ranging from 7.592 ± 0.32 to 16.006 ± 0.58 µM comparable to that of erlotinib (IC₅₀ ranging from 4.99 ± 0.09 to 13.914 ± 0.36 µM). Furthermore, the most potent antitumor agent (13k) was selected for further studies to determine its effect on the cell cycle progression and apoptosis in MCF-7 cell line. The results indicated that this compound arrests G₂/M phase of the cell cycle and it is a good apoptotic agent. Finally, molecular docking studies showed a good binding pattern of the synthesized compounds with the prospective target, EGFR^WT and EGFR^T790M.     

Dihydrofolate reductase inhibition effect of 5-substituted pyrido[2,3-d]pyrimidines: Synthesis,antitumor activity and molecular modeling study

A new series of pyrido[2,3-d]pyrimidines 3–18 bearing substitution at C-5 position was synthesized. All compounds were tested for their in vitro antitumor activity against five human cancer cell lines namely; hepatocellular carcinoma (HePG2), breast carcinoma (MCF-7), human prostate carcinoma (PC3), colorectal carcinoma (HCT-116), and cervical carcinoma (Hela) using doxorubicin as a positive control. Compounds 3, 4, 9, 11, 13, 14, 15 and 17 exhibited the highest antitumor activity against the tested cell lines and were selected to screen their enzymatic inhibition against dihydrofolate reductase enzyme (DHFR) compared with the reference drug methotrexate (MTX), to explain the probable mechanism of action of the observed anticancer activity. Compound 11 displayed the highest inhibitory activity (IC₅₀ = 6.5 µM) among the tested compounds in comparison with MTX (IC₅₀ = 5.57 µM). Also, compounds 13 and 14 showed high inhibitory activity against DHFR with IC₅₀ values 7.1 and 8.7 µM, respectively. Comparative molecular modeling study was performed between DHFR inhibitors 11, 13 and 14 of the highest activity and 10 of the lowest activity among the eight inhibitors against MTX. Docking studies into the active site of DHFR domain showed good agreement with the obtained biological results. Finally, compound 11 was found to be best antitumor, DHFR inhibitor, and it induced the process of apoptosis at Pre-G phase and cell cycle arrest at G2/M phase in MCF-7 cells.     

1,2,3-triazole tethered Indole-3-glyoxamide derivatives as multiple inhibitors of 5-LOX,COX-2 & tubulin: Their anti-proliferative & anti-inflammatory activity

To evaluate the role of COX-2 and 5-LOX as dual inhibitors in controlling the cancer cell proliferation, a set of two series having 42 compounds of 1, 2, 3-Tethered Indole-3-glyoxamide derivatives were synthesized by employing click chemistry approach and were also evaluated for their in vitro cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) inhibitory activities with in vivo anti-inflammatory and in vitro anti-proliferative potencies. Among the compounds tested, compounds 11q and 13s displayed excellent inhibition of COX-2 (IC₅₀ 0.12 µM) with good COX-2 selectivity index (COX-2/COX-1) of 0.058 and 0.046 respectively. Compounds 11q and 13s also demonstrated comparable 5-LOX inhibitory activity with IC₅₀ 7.73 and 7.43 µM respectively to that of standard Norhihydroguaiaretic acid (NDGA: IC₅₀ 7.31 µM). Among all the selected cell lines, prostate cancer cell line DU145 was found to be susceptible to this class of compounds. Among all the tested compounds, compounds 11g, 11i, 11k, 11q, 13r, 13s and 13u demonstrated excellent to moderate anti-proliferative activity with IC_50s ranging between 6.29 and 18.53 µM. Compounds 11q and 11g demonstrated better anti-proliferative activities against DU145 cancer cell line with IC₅₀ values 8.17 and 8.69 µM respectively when compared to the standard drug etoposide (VP16; IC₅₀ 9.80 µM). Compounds 11g, 11k, 11q, 13s and 13u showed good dual COX-2/5-LOX inhibitory potentials with excellent anti-proliferative activity. Results from carrageenan-induced hind paw edema demonstrated that compounds 11b, 11l, 11q and 13q exhibited significant anti-inflammatory activity with 69–77% inhibition at 3 h, 75–82% inhibition at 5 h when compared to the standard drug indomethacin (66.6% at 3 h and 77.94% at 5 h). Ulcerogenic study revealed that compounds 11q and 13q did not cause any gastric ulceration. In vitro tubulin assay resuted that compound 11q interfered with microtubulin dynamic and act as tubulin polymerization inhibitor. In silico molecular docking studies demonstrated that compounds 11q and 13s are occupying the colchicines binding site of tubulin polymer and 11q illustrated very good binding affinities towards COX-2 and 5-LOX.     

Synthesis and anticancer activities of thieno[3,2-d]pyrimidines as novel HDAC inhibitors

A series of thieno[3,2-d]pyrimidines bearing a hydroxamic acid moiety as novel HDAC inhibitors were designed and synthesized. The structures of the new synthesized compounds were confirmed using IR, ¹H, ¹³C NMR spectrum. Compounds 11–13 showed potent inhibitory activities against HDACs with IC₅₀ values at 0.38, 0.49 and 0.61 μM. Most of target compounds displayed strong anti-proliferative activity by a MTT assay on three human cancer cell lines including HCT-116, MCF-7 and HeLa. Compound 11, having potent inhibitory activities against HDACs, induced apoptosis and G2/M cell cycle arrest in HCT-116 cell line.     

Cytotoxicity and inhibition of DNA topoisomerase I of polyhydroxylated triterpenoids and triterpenoid glycosides

Cytotoxicity and inhibition on human DNA topoisomerase I (TOP1) and II (TOP2) of 74 plant-originated triterpenoids and triterpenoid glycosides were investigated. The cytotoxic compounds are primarily polyhydroxylated oleananes (GI₅₀ of A549: 1.0–10.19 μM). Sixteen cytotoxic aesculiosides isolated from Aesculus pavia inhibited TOP1 catalytic activity by interacting directly with the free enzyme and preventing the formation of the DNA–TOP1 complex. Interestingly, hydrolysis of six active aesculiosides (1, 4, 6, 8, 10, and 23) lost their TOP1 activities but enhanced their cytotoxicities. None of the test compounds showed any activity against TOP2. Structure–activity relationship (SAR) investigations indicated that cytotoxic oleananes required at least one angeloyl moiety at either C-21 or C-22 but the sugar moiety at C-3 may decrease their cytotoxicities. An angeloyl or tigeloyl group at C-21 is required for oleananes to bind the free TOP1 enzyme although the type and length of acyl moiety at C-22 also affects their activity. However, sugar moiety at C-3 is necessary for their TOP1 activities.     

Synthesis and biological evaluation of tetracyclic fluoroquinolones as antibacterial and anticancer agents

A simple and efficient synthesis of 6-fluoro-4-oxopyrido[2,3-a]carbazole-3-carboxylic acids (13a–e) and a structurally related 6-fluoro-4-oxothieno[2′,3′:4,5]pyrrolo[3,2-h]quinoline (13f) was achieved via Stille arylation of 7-chloro-6-fluoro-8-nitro-4-oxoquinoline-3-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. The ability of 13a–f to inhibit the activity of DNA gyrase and topoisomerase IV was also investigated. The thieno isostere (13f) emerged as the most active antibacterial, while the 9-fluoro derivative (13e) was the most potent against multidrug-resistant staphylococci. Compounds 13a, 13c–f displayed growth inhibition against MCF-7 breast tumor and A549 non-small cell lung cancer cells coupled with an absence of cytotoxicity toward normal human-derm fibroblasts (HuDe). Compound 13e was the most active anticancer against MCF-7 cells, with greater potency than ellipticine (IC₅₀ 0.8 and 1.6 μM, respectively). The most active compounds in this series show promise as dual acting anticancer and antibacterial chemotherapeutics.     

Novel carbazole sulfonamide derivatives of antitumor agent: Synthesis,antiproliferative activity and aqueous solubility

The current optimization of IG-105 (3) on the carbazole-ring provided a series of new carbazole sulfonamides derivatives 13a–13m. All of the compounds have been evaluated against HepG2 cells (hepatoma cancer) for antiproliferative activity. Compounds that showed activity better or comparable to that of 3 versus HepG2 were evaluated against MCF-7 (breast cancer), MIA PaCa-2 (pancreatic cancer), and Bel-7402 (hepatoma/liver cancer) for antiproliferative activity. Of the seven compounds selected for further study five (13b, 13g, 13j, 13k and 13l) were found to give IC₅₀ values against the four cell lines comparable to those for 3. Two compounds (13f and 13i) were more active than 3 and their activity against HepG2 and MCF-7 (IC₅₀:0.01–0.07 μM) approached that of the positive controls podophyllotoxin (podo) and CA-4. Most of compounds showed aqueous solubility (0.11–19.60 μg/mL at pH 7.4 and 2.0) better than 3. These promising results warrant further development of new compounds 13f and 13i as potential potent antitumor drug candidates.     

Synthesis and comparative carbonic anhydrase inhibition of new Schiff’s bases incorporating benzenesulfonamide,methanesulfonamide, and methylsulfonylbenzene scaffolds

Herein, we report the synthesis, characterization, and carbonic anhydrase (CA) inhibition of the newly synthesized Schiff’s bases 4–18 with benzenesulfonamide, methanesulfonamide, and methylsulfonylbenzene scaffolds. The compound inhibition profiles against human CA (hCA) isoforms I, II, IX, and XII were compared to those of the standard inhibitors, acetazolamide (AAZ) and SLC-0111 (a CA inhibitor in Phase II clinical trials for the treatment of hypoxic tumors). The hCA I was inhibited by compounds 4a–8a with inhibition constants (K_I) in the range 93.5–428.1 nM (AAZ and SLC-0111: K_I, 250.0 and 5080.0 nM, respectively). Compounds 4a–8a proved to be effective hCA II inhibitors, with K_I ranging from 18.2 to 133.3 nM (AAZ and SLC-0111: K_I, 12.0 and 960.0 nM, respectively). Compounds 4a–8a effectively inhibited hCA IX, with K_I in the range 8.5–24.9 nM; these values are superior or equivalent to that of AAZ and SLC-0111 (K_I, 25.0 and 45.0 nM, respectively). Compounds 4a–8a displayed effective hCA XII inhibitory activity with K_I values ranging from 8.6 to 43.2 nM (AAZ and SLC-0111: K_I, 5.7 and 4.5 nM, respectively). However, compounds 9b–13b and 14c–18c were found to be micromolar CA inhibitors. For molecular docking studies, compounds 5a, 6a, and 8a were selected.     

Studies on non-steroidal inhibitors of aromatase enzyme; 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives

Steroidal and non-steroidal aromatase inhibitors target the suppression of estrogen biosynthesis in the treatment of breast cancer. Researchers have increasingly focused on developing non-steroidal derivatives for their potential clinical use avoiding steroidal side-effects.Non-steroidal derivatives generally have planar aromatic structures attached to the azole ring system. One part of this ring system comprises functional groups that inhibit aromatization through the coordination of the haem group of the aromatase enzyme. Replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase selectivity over aromatase enzyme inhibition.In this study, 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives were synthesized and physical analyses and structural determination studies were performed. The IC₅₀ values were determined by a fluorescence-based aromatase inhibition assay and compound 1 (4-(2-hydroxyphenyl)-2-(pyrimidine-2-yl)thiazole) were found potent inhibitor of enzyme (IC₅₀:0.42?nM). Then, their antiproliferative activity over MCF-7 and HEK-293 cell lines was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Compounds 1, 7, 8, 13, 15, 18, 21 were active against MCF-7 breast cancer cells. Lastly, a series of docking experiments were undertaken to analyze the crystal structure of human placental aromatase and identify the possible interactions between the most active structure and the active site.     

Synthesis and anti-inflammatory activity of sulfonamides and carboxylates incorporating trimellitimides: Dual cyclooxygenase/carbonic anhydrase inhibitory actions

Trimellitimides 6–21 were prepared and investigated in vivo for anti-inflammatory and ulcerogenic effects and in vitro for cytotoxicity. They were subjected to in vitro cyclooxygenase (COX-1/2) and carbonic anhydrase inhibition protocols. Compounds 6–11 and 18 exhibited anti-inflammatory activities and had median effective doses (ED₅₀) of 34.3–49.8 mg kg⁻¹ and 63.6–86.6% edema inhibition relative to the reference drug celecoxib (ED₅₀: 33.9 mg kg⁻¹ and 85.2% edema inhibition). Compounds 6–11 and 18 were weakly cytotoxic at 10 μM against 59 cell lines compared with the reference standard 5-fluorouracil (5-FU). Compounds 6–11 had optimal selectivity against COX-2. The selectivity index (SI) range was >200–490 and was comparable to that for celecoxib [COX-2 (SI) > 416.7]. In contrast, compounds 12, 13, and 16–18 were nonselective COX inhibitors with a selectivity index range of 0.92–0.25. The carbonic anhydrase inhibition assay showed that sulfonamide incorporating trimellitimides 6–11 inhibited the cytosolic isoforms hCA I and hCA II, and tumor-associated isoform hCA IX. They were relatively more susceptible to inhibition by compounds 8, 9, and 11. The K_I ranges were 54.1–81.9 nM for hCA I, 25.9–55.1 nM for hCA II, and 46.0–348.3 nM for hCA IX. © 2018 Elsevier Science. All rights reserved.     

Chemical constituents from Laggera pterodonta

A phytochemical investigation on the aerial parts of Laggera pterodonta resulted in the isolation and identification of fourteen compounds, including six sesquiterpenoids (1–6), five flavonoids (7–11), one lignan (12), and two pyrrole alkaloids (13, 14). Among them, compounds 1–3, 7–9, and 11 are the characteristic class of secondary metabolites of L. pterodonta. Compounds 4 and 5 were firstly isolated from L. pterodonta and this is the first report of the presence of compounds 6, 10, and 12 from the genus Laggera. Pyrrole alkaloids 13 and 14 may serve as potential chemotaxonomic markers for L. pterodonta and could be used to distinguish among species of Compositae.     

Design,synthesis, molecular modeling and biological evaluation of novel 1H-pyrazolo[3,4-b]pyridine derivatives as potential anticancer agents

In trying to develop new anticancer agents, a series of 1H-pyrazolo[3,4-b]pyridine derivatives was designed and synthesized. Fifteen compounds were evaluated in vitro for their anti-proliferative activity against HePG-2, MCF-7, HCT-116, and PC-3 cell lines. Additionally, DNA binding affinity of the synthesized derivatives was investigated as a potential mechanism for the anticancer activity using DNA/methyl green assay and association constants assay. Compounds 19, 20, 21, 24 and 25 exhibited good activity against the four cancer cells comparable to that of doxorubicin. Interestingly, DNA binding assay results were in agreement with that of the cytotoxicity assays where the most potent anticancer compounds showed good DNA binding affinity comparable to that of doxorubicin and daunorubicin. Furthermore, a molecular docking of the tested compounds was carried out to investigate their binding pattern with the prospective target, DNA (PDB-code: 152d).     

Dual VEGFR-2/PIM-1 kinase inhibition towards surmounting the resistance to antiangiogenic agents via hybrid pyridine and thienopyridine-based scaffolds: Design,synthesis and biological evaluation

Angiogenesis is a hallmark in cancer. Most antiangiogenic agents block the action of vascular endothelial growth factor (VEGF). In clinic, patients develop hypoxia-mediated resistance consistent with vascular responses to these agents. Recent studies underlying such resistance revealed hypoxia-inducible PIM-1 kinase upregulation which promotes cancer progression. PIM-1 kinase expression is thus viewed as a new resistance mechanism to antiangiogenic agents. Hence, combining PIM kinase inhibitors with anti-VEGF therapies provides synergistic antitumor response. Inspired by these facts, the current study aims at designing novel dual VEGFR-2/PIM-1 kinase inhibitors via molecular hybridization and repositioning of their pharmacophoric features. Moreover, enhancing the cytotoxic potential of the designed compounds was considered via incorporating moieties mimicking caspase 3/7 activators. Accordingly, series of novel pyridine and thieno[2,3-b]pyridine derivatives were synthesized and screened via MTT assay for cytotoxic activities against normal fibroblasts and four cancer cell lines (HepG-2, Caco-2, MCF-7 and PC-3). Compounds 3a, 9e, 10b and 10c exhibited anticancer activities at nanomolar IC₅₀ with promising safety, activated caspase 3/7 and induced apoptosis as well as DNA fragmentation more than doxorubicin in the four cancer cell lines. Furthermore, they exerted promising dual VEGFR-2/PIM-1 kinase inhibition and significantly exhibited higher therapeutic potential to alter the expression levels of VEGF, p53 and cyclin D than doxorubicin. Interestingly, the most active anticancer compound 10b conferred the highest dual VEGFR-2/PIM-1 kinase inhibition. Finally, their in silico ligand efficiency metrics were acceptable.     

New coumestan and coumaronochromone derivatives from Dalbergia boehmii Taub. (Fabaceae)

Chemical investigation of leaves and heartwood of Dalbergia boehmii resulted in the isolation of two new phenolic compounds, designated dalbergestan (1) and dalbergichromone (2), along with eleven known compounds, carpachromene (3), proanthocyanidin A-2 (4); piceatannol (5); biochanin A (6); macckiain (7); homopterocarpin (8); angolensin (9); medicarpin (10); 2′,7-dihydroxy-4′,5′-dimethoxyisoflavone (11); 2′-methoxyformononetin (12); and genistein (13). The structures of the new compounds were elucidated on the basis of extensive spectroscopic analyses including, IR, UV, 1D and 2D – NMR as well as HRMS data. Some of the isolated compounds were evaluated for their in vitro insulin secretion activity on isolated mice islets, leishmanicidal activity against L. major (DESTO) promastigotes and in vitro cytotoxicity on MCF-7 cell lines. All tested compounds were inactive on glucose-stimulated insulin secretion at stimulatory glucose (20.0 mM) from MIN6 cells. Compounds 3 (IC₅₀, 70.0 μg/ml), 6 (IC₅₀, 60.3 μg/ml), 7 (IC₅₀, 86.5 μg/ml) and 13 (IC₅₀, 62.6 μg/ml) exhibited low leishmanicidal activity while compound 12 (IC₅₀, 56.8 μg/ml) displayed a moderate activity. Compounds 3 and 5 were found to be active against MCF-7 at 50 μM with IC₅₀ value 33.2 ± 3.79 μg/ml and 42.64 ± 5.05 μg/ml respectively.