Propyl Linker Research Articles

Anticancer and anti-inflammatory effects of novel ethyl pyrazole derivatives having sulfonamide terminal moiety

In the present work, a new series of ethyl pyrazole-containing compounds with side sulphonamide moiety was designed and synthesized. The new derivatives were divided into four groups based on the linker between the sulphonamide and pyridine ring attached to position 4 of the pyrazole ring and the substitution on the phenyl ring at position 3 of the same ring. The linker could be ethyl or propyl linkers. The phenyl ring is substituted with a methoxy group or hydroxyl group at position 3. The aim compounds were tested for their JNK1, JNK2, JNK3, and BRAF(V600E) activities. Compounds 23b, 23c, and 23d showed the highest activity with nanomolar IC50s. The most potent compound over JNK1 was 23d with an IC502 nM. While compound 23c was the most potent over JNK2 with an IC5057 nM. Finally, compound 23b was the most potent over JNK2 and BRAF(V600E) with IC50s of125 nM and 98 nM, respectively. After obtaining kinase inhibitory activity, the compounds were submitted to NCI to test their activity over different cell lines. Compound 23b showed the highest activity over most tested cell lines. In the second part of the present study, the final target compounds were tested for their anti-inflammatory effect. The anti-inflammatory effect of the new final compounds was performed by measuring their ability to inhibit inducible nitric oxide release and prostaglandin E2 production inhibition. Compound 23c showed the highest activity regarding nitric oxide release with IC50 0.63 μM, while compound 21d had the highest activity regarding prostaglandin E2 production with IC50 0.52 μM. The effect of the most potent compounds was tested by western blot against iNOS, COX-1, and COX-2.

Synthetic routes to carbon substituted cobalt bis(dicarbollide) alkyl halides and aromatic amines along with closely related irregular pathways.

Carbon substituted cobalt bis(dicarbollide) alkyl halides [(1-X-(CH2)n-1,2-C2B9H10)(1,2-C2B9H11)-3,3'-Co]Me4N (X = Br, I; n = 1-3) are prepared in high yields (>90%) from their corresponding alcohols without side skeletal substitutions. These species offer access to the synthesis of aromatic cobalt bis(dicarbollide) amines, however only for particular terminal halogen substitution, the propylene pendant arm, and under appropriately controlled reaction conditions. Thus, the compounds substituted at cage carbon atoms with a propylene linker and terminal aromatic amine groups could be prepared. In other cases, numerous irregular reaction pathways occur, undoubtedly as a consequence of the bulky anionic boron cage in close proximity to the reaction site. Among them, an unusual intramolecular hydroboration forming rigidified carbon-to-boron bridged isomeric anions with an asymmetric structure that correspond to formulae [(1,8'-μ-C2H4)-(1,2-C2B9H10)(1',2'-C2B9H10)-3,3'-Co]- and [(1,7'-μ-C2H4)-(1,2-C2B9H10)(1',2'-C2B9H10)-3,3'-Co]- is described herein and the former isomer is structurally characterized. This product with a restrained geometry is widely accessible through nucleophile and/or thermally induced decomposition of (pseudo)halides attached to the cage via an ethylene linker. Surprisingly enough, also doubly bridged isomeric species [(1,8-μ-C2H4-1,2-C2B9H9)2-3,3'-Co]- and [(1,7-μ-C2H4-1,2-C2B9H9)2-3,3'-Co]- are available in good yield using these methods. Furthermore, other more typical side reactions are discussed, i.e. nucleophilic reactions of propyl halides with Me3N formed apparently by disproportionation of Me4N+ at higher temperatures or with pyridine used as a base.

Investigating the role of indole and quinazolinone-based hybrid analogues with ketoamide fragment and alkyl extension for potential PL inhibition

Pancreatic lipase (PL) is a key enzyme responsible for the digestion of dietary fat. Hence the inhibition of PL is an effective strategy for mitigating obesity. In this study, a novel series of 18 indolyl oxoacetamide–quinazolinone hybrid analogues (9a-h, 13aa-13fd) were designed, synthesized, and evaluated for PL inhibition activity. An approach of molecular hybridization was utilized by considering the PL inhibitory potential of indole, α-ketoamide, and quinazolinone scaffolds. A Propyl linker was attached for better binding at the PL active site, leading to enhanced PL inhibitory potential. Among all the synthesized analogues, 13be exhibited the highest PL inhibitory activity (IC50 = 4.71 ± 0.851 μM) with a docking score of -147.06 kcal/mol. The activities of all the synthesized analogues were compared with the orlistat (IC50 = 0.86 ± 0.090 µM). The most potent analogue, 13be revealed the competitive mode of enzyme inhibition with the Ki value of 1.826 µM. The molecular docking and dynamics simulation analysis also revealed the strong binding of 13be at the active site of PL. Interestingly, the potent analogue 13be when tested on RAW 264.7 cell line using MTT assay, was found to be nontoxic at a concentration range of 1-20 µM. Therefore, the current work validates the effectiveness of the molecular hybridization approach for designing indolyl oxoacetamide–quinazolinone hybrids for inhibiting PL.

Diamine-appended metal-organic framework for carbon capture from wet flue gas: Characteristics and mechanism

Due to the superior CO2 adsorption capacity and selectivity, amine-functional solid adsorbents have received increasing attention. Nevertheless, amine-functionalized polyporous materials have a large performance deviation when considering carbon removal capacity under wet flue gas. Therefore, a variety of metal–organic frameworks (MOFs) with amine functionality are synthesized in this work by appending diamine with a propylene linker to Mg2(dobpdc) (dobpdc4- = 4,4′-dioxido-3,3′-biphenyldicarboxylate) and screened under the simulated flue gas environment with a high water content (7 v%). The results indicate that ndmpn-grafted Mg2(dobpdc) (ndmpn = N,N-dimethyl-1,3-propanediamine) has a high CO2 adsorption capacity of 1.72 mmol/g at 60 °C with an extremely low regeneration heat (2.26 GJ/ton CO2 at the desorption temperature of 145 °C). Adsorption property of ndmpn-Mg2(dobpdc) at high humidity is even more excellent than that of another well-reported diaminopropene-appended MOF, dmpn-Mg2(dobpdc) (dmpn = 2,2-dimethyl-1,3-propanediamine). Herein, van der Waals (vdW)-corrected density functional theory (DFT) calculations are used to quantitatively analyze binding strengths and water effects on it between diamine-appended Mg2(dobpdc) and CO2. It is revealed that the addition of water makes ammonium carbamate chains produced in ndmpn-Mg2(dobpdc) more stable. These chemisorption structures under humid conditions have also been disclosed by using 15N solid-state nuclear magnetic resonance (NMR) spectroscopy experiments and DFT calculation. To conclude, we unveil the binary adsorption characteristics and mechanism of ndmpn-Mg2(dobpdc). It enables a thorough understanding of this compound and highlights its potential as a promising adsorbent under humid conditions for post-combustion applications.

Anti-inflammatory effect of 3-fluorophenyl pyrimidinylimidazo[2,1-b]thiazole derivatives as p38α inhibitors

In the present work, the anti-inflammatory effect of 30 compounds containing 3-fluorophenyl pyrimidinylimidazo[2,1-b]thiazole was investigated. All final target compounds showed significant Inhibitory effect on p38α. P38α is considered one of the key kinases in the inflammatory process due to its regulatory effect on pro-inflammatory mediators. The final target compounds divided into four group based on the type of terminal moiety (amide and sulfonamide) and the linker between pyrimidine ring and terminal moiety (ethyl and propyl). Most compounds with terminal sulfonamide moiety and propyl linker between the sulfonamide and pyrimidine ring were the most potent among all synthesized final target compounds with sub-micromolar IC50s. Compound 24g (with p-Cl benzene sulfonamide and propyl linker) exhibited the highest activity over P38α with IC50 0.68 µM. All final target compounds were tested for their ability to inhibit nitric oxide release and prostaglandin E2 production. Compounds having amide terminal moiety with ethyl linker showed higher inhibitory activity for nitric oxide release and compound 21d exhibited the highest activity for nitric oxide release with IC50 1.21 µM. Compounds with terminal sulfonamide moiety and propyl linker showed the highest activity for inhibiting PGE2 production and compounds 24i and 24g had the lowest IC50s with value 0.87 and 0.89 µM, respectively. Compounds 21d, 22d and 24g were tested for their ability to inhibit over expression of iNOS, COX1, and COX2. In addition the ability of compounds 21d, 22d and 24g to inhibit inflammatory cytokines were determined. Finally molecular docking of the three compounds were performed on P38α crystal structure to expect their mode of binding.

Mitochondria-targeted derivative of pterostilbene, a dietary phytoestrogen, exhibits superior cancer cell cytotoxicity via mitochondrial superoxide mediated induction of autophagy

Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene;PTS), a dimethyl ether analogue of resveratrol, has been shown to possess anti-bacterial, anti-cancer, anti-inflammatory and antioxidant properties. In the present study, we have synthesized a mitochondria targeted derivative of Pterostilbene (M-PTS) with aim to enhance its anti-cancer efficacy. M-PTS was synthesized by substituting the free hydroxyl group of PTS with a propyl linker and Triphenylphosphonium (TPP+, a membrane-permeable lipophilic cation that readily accumulates and penetrates through the mitochondrial membrane). We observed that mitochondrial uptake of M-PTS in A549 cells was higher (∼8.5-fold) as compared to PTS and M-PTS was more potent in killing human lung (A549) and breast (MCF-7) cancer cells as compared to PTS. IC50 of M-PTS was found to be 0.17 µM and 0.76 µM, respectively, while IC50 of PTS was found to be 40.45 µM and 53.15 µM in A549 and MCF-7 cells, respectively. M-PTS was superior in inhibiting the clonogenic potential of A549 and MCF-7 cell and M-PTS induced apoptosis in A549 cells. M-PTS specifically increased both cytosolic ROS and mitochondrial superoxide levels whereas PTS did not have any effect on mitochondrial superoxide. M-PTS treatment led to autophagy induction in cancer cells. M-PTS induced cytotoxicity was attenuated on pre-treatment with mitochondria-targeted antioxidant (mitoTEMPO) as well as inhibitor of autophagy (chloroquine) signifying the involvement of mitochondrial ROS and autophagy in the cytotoxic effects of M-PTS. In conclusion, the superior cytotoxic efficacy of M-PTS via specific induction of mitochondrial superoxide illustrates the application of mitochondria targeted redox-active natural products as potent anti-cancer drugs.

Synthesis, Molecular Docking and ADME Prediction of 1H-indole/5- substituted Indole Derivatives as Potential Antioxidant and Anti- Inflammatory Agents.

Inflammation is a protective biological process, but under extreme conditions, it can become highly dreadful to the body. Antioxidant and anti-inflammatory agents treat similar disease conditions as inflammation and oxidative stress commonly follow similar causative pathways. The goal of this study was to synthesize N-substituted indole derivatives with different heterocyclic moieties through propyl linker with the aim of getting highly potent anti-inflammatory and antioxidant agents. Synthesized compounds were analyzed by analytical techniques such as IR, 1H NMR, 13C NMR spectra, and mass spectrometry. Molecular docking and ADME calculation were employed on synthesized compounds to estimate their COX-2 enzyme inhibition and drug like properties, respectively. Antioxidant activity was evaluated by the DPPH assay and the reducing power assay. Selected derivatives were evaluated for anti-inflammatory activity at an acute (carrageenan-induced paw edema method) and chronic level (formalin-induced inflammation method) using indomethacin as a standard drug. Herein, twelve indole derivatives (11a-c, 12a-c, 13a-c, and 14a-c) were synthesized. Among all, compound 12c was found to be the best inhibitor of the COX-2 enzyme as it displayed good interaction energy. Zero violations of Lipinski's rule were found in the ADME investigation, confirming the drug-like qualities of synthesized compounds. The compounds 11a and 12c were found to be the most potent as compared with standard ascorbic acid in antioxidant evaluation. From the collected results, compounds 12c and 13b were the most potent against acute and chronic inflammation. The novel synthetic indole derivatives could act as potent leads for the development of novel antioxidant and anti-inflammatory agents.

Anion binding and transport with meso-alkyl substituted two-armed calix[4]pyrroles bearing urea and hydroxyl groups.

Calix[4]pyrroles bearing hydroxyl (1) or urea (3) groups attached to the meso-positions with propyl linkers were synthesized as cis- and trans-isomers. The anion binding properties of cis-1 and cis-3 were screened with ion-mobility mass spectrometry, where cis-1 formed complexes with Cl-, Br- and H2PO4-, whereas cis-3 formed complexes with most of the investigated anions, including Cl-, Br-, I-, NO3-, ClO4-, OTf-, SCN- and PF6-. The structures of the chloride complexes were further elucidated with density functional theory calculations and a crystal structure obtained for cis-1. In solution, chloride and dihydrogenphosphate anion binding with cis-1 and cis-3 were compared using 1H NMR titrations. To assess the suitability of two-armed calix[4]pyrroles as anion transporters, chloride transport studies of cis-1, cis-3 and trans-3 were performed using large unilamellar vesicles. The results revealed that cis-3 had the highest activity among the investigated calix[4]pyrroles, which was related to the improved affinity and isolation of chloride inside the binding cavity of cis-3 in comparison to cis-1. The results indicate that appending calix[4]pyrroles with two hydrogen bonding arms is a feasible strategy to obtain anion transporters and receptors with high anion affinity.

Design and synthesis of a new series of hybrids of functionalised N1-[(1H-1,2,3-triazol-4-yl)methyl]quinazoline-2,4-dione with antiviral activity against Respiratory Syncytial Virus

In this study, a series of 48 hybrids of the functionalised 1-[(1H-1,2,3-triazole-4-yl)methyl]quinazoline-2,4-dione 17–22 were synthesised and evaluated for potential antiviral activity. The new hybrids were designed to contain a diethoxyphosphoryl group connected to the triazole moiety via ethylene or propylene linker, and in which the benzyl or benzoyl function is substituted at N3 in the quinazoline-2,4-dione moiety. The Cu(I)-catalyzed Hüisgen dipolar cycloaddition of azidophosphonates 23 and 24 with the respective N1-propargylquinazoline-2,4-diones 26aa–26ag, 26ba–26bg, 27aa–27ad and 27ba–27bd was applied for the syntheses of the designed compounds. All final hybrids 17–22 and N3-functionalised N1-propargylquinazoline-2,4-diones 26 and 27 were subsequently evaluated for their antiviral activity toward a broad range of DNA and RNA viruses. Importantly, hybrids 19be–19bg and 20be–20bg showed profound antiviral activities against Respiratory Syncytial Virus (RSV) with EC50 values in the lower micromolar range, with activity against viral strains of both subtypes (RSV A and B). In addition, several compounds also exerted some weak antiviral activity against varicella zoster virus. Finally, 19 ag was the only compound that showed antiviral potency against human cytomegalovirus, although with rather weak inhibitory activity. Notably, none of the tested compounds was cytotoxic toward uninfected cell lines used for the antiviral assays at a concentration up to 100 μM, returning interesting therapeutic indices for respiratory syncytial virus.

"Dynamical Docking" of Cyclic Dinuclear Au(I) Bis-N-heterocyclic Complexes Facilitates Their Binding to G-Quadruplexes.

With the aim to improve the design of metal complexes as stabilizers of noncanonical DNA secondary structures, namely, G-quadruplexes (G4s), a series of cyclic dinuclear Au(I) N-heterocyclic carbene complexes based on xanthine and benzimidazole ligands has been synthesized and characterized by various methods, including X-ray diffraction. Fluorescence resonance energy transfer (FRET) and CD DNA melting assays unraveled the compounds' stabilization properties toward G4s of different topologies of physiological relevance. Initial structure-activity relationships have been identified and recognize the family of xanthine derivatives as those more selective toward G4s versus duplex DNA. The binding modes and free-energy landscape of the most active xanthine derivative (featuring a propyl linker) with the promoter sequence cKIT1 have been studied by metadynamics. The atomistic simulations evidenced that the Au(I) compound interacts noncovalently with the top G4 tetrad. The theoretical results on the Au(I) complex/DNA Gibbs free energy of binding were experimentally validated by FRET DNA melting assays. The compounds have also been tested for their antiproliferative properties in human cancer cells in vitro, showing generally moderate activity. This study provides further insights into the biological activity of Au(I) organometallics acting via noncovalent interactions and underlines their promise for tunable targeted applications by appropriate chemical modifications.

Tranilast-tyrosine hybrid molecule exhibits dual activity: suppression of epithelial-mesenchymal transition and induction of cytotoxicity in cancer cells

The anti-allergic drug tranilast (TNL) reportedly exhibits inhibitory activity against epithelial-mesenchymal transition (EMT) at high concentrations. Herein, we synthesized a new hybrid molecule, tyrosine-conjugated TNL having a propyl linker (TNL-T), which is expected to increase anti-EMT activity by enhancing intracellular delivery through an amino acid transporter expressed in cancer cells. The anti-EMT activity of TNL-T was similar to that of TNL in the lung carcinoma cell line A549. Unlike TNL, TNL-T could induce dose-dependent cytotoxicity in A549 cells; this cytotoxicity was also observed in the glioblastoma cell lines U251 and U87. However, neither tyrosine nor TNL exhibited such cytotoxicity, demonstrating the importance of the TNL-T structure. The derivatization study showed that a derivative with an ethyl linker has the similar functions, and that of a pentyl linker was inactive. TNL-T, which exhibited dual activity by suppressing EMT and cancer cell proliferation, could aid in the development of new anticancer drugs.

Characterization of the Interactions between an Unassociated Cationic Pyrene-Labeled Gemini Surfactant and Anionic Sodium Dodecyl Sulfate.

The gemini surfactant PyO-3-12, made of two dimethylammonium bromides joined by a propyl linker and bearing a dodecyl pendant on one side and a 1-pyrenemethoxyhexyl group on the other side, was employed to probe the interactions between positively charged PyO-3-12 and negatively charged sodium dodecyl sulfate (SDS). PyO-3-12 was selected for its ability to respond to the polarity of its local environment through the fluorescence intensity ratio I1/I3 of the first-to-third fluorescence peaks of the pyrene monomer and the local pyrene concentration [Py]loc through the IE/IM ratio of the pyrene excimer-to-pyrene monomer fluorescence intensity. Furthermore, analysis of the fluorescence decays of aqueous solutions of PyO-3-12 and SDS yielded a measure of the internal dynamics, local concentration, and state (associated vs unassociated) of PyO-3-12 in solution. By following these parameters for aqueous solutions prepared with a constant PyO-3-12 concentration of either 1, 4, or 16 μM and SDS concentrations ranging from 0 to 200 mM, six SDS concentration regimes were identified to describe the interactions between PyO-3-12 and SDS in pure water. Sharp transitions of the parameters describing the fluorescence of pyrene marked the boundaries between the different regimes. Perhaps the most important transition was the one defining the formation of the PyO-3-12/SDS aggregates, which was completed at the equicharge point, implying that they were constituted of 1 meq of PyO-3-12 and 2 meq of SDS. The low I1/I3 ratio obtained for the PyO-3-12/SDS aggregates suggested that they were multilamellar aggregates, which would shield the pyrenyl labels from polar water. The formation of these multilamellar aggregates was confirmed by transmission electron microscopy (TEM), which demonstrated the existence of multilamellar vesicles, whose presence increased with decreasing PyO-3-12 concentration. This study suggests that the combination of pyrene excimer formation and TEM provides an interesting experimental means to probe the assemblies generated from oppositely charged surfactants at surfactant concentrations, which are much lower than their critical micelle concentration.

3,5-Bis(trifluoromethyl)phenylsulfonamides, a novel pancreatic cancer active lead. Investigation of the terminal aromatic moiety

Virtual screening identified N-(6-((4-bromobenzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzenesulfonamide (1) a lead compound that bound to the S100A2-p53 binding groove. S100A2 is a Ca2+ binding protein with implications in cell signaling and is known to be upregulated in pancreatic cancer. It is a validated pancreatic cancer drug target. Lead 1, inhibited the growth of the MiaPaCa-2 pancreatic cancer cell line (GI50 = 2.97 μM). Focused compound libraries were developed to explore the SAR of this compound class with 4 libraries and 43 compounds total.Focused library (Library 1) development identified lipophillic sulfonamides as preferred for MiaPaCa-2 activity, with -CF3 and -C(CH3)3 substituents well tolerated (MiaPaCa-2 GI50 < 6 μM). Contraction of the hexylamino spacer to ethyl (Library 2) and propyl (Library 3) proved beneficial to activity against a broad spectrum panel of cancer cell lines: HT29 (lung), MCF-7 (breast), A2780 (ovarian), H460 (colon), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma), U87 and SJ-G2 (glioblastoma) (cohort-1); and a pancreatic cancer cell line panel: MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, HPAC and PANC-1 (cohort-2). With a marked preference for a propyl linker the observed GI50 values ranged from 1.4 to 30 μM against cohort-1 and 1.4–30 μM against cohort-2 cell lines. In Library 4 the terminal aromatic moiety was explored with 4-substituted analogues preferred (with activity of 48 (4-Cl) > 47 (3-Cl) > 46 (2-Cl)) against the cell lines examined. The introduction of bulky aromatic moieties was well tolerated, e.g. dihydrobenzo[b][1,4]dioxine (51) returned cohort-2 GI50 values of 1.2–3.4 μM. In all instances the observed docked binding poses and binding scores were consistent with the observed cytotoxicity. This in turn supports, but does not prove, that these analogues function via S100A2-p53 binding groove inhibition.

Synthesis of Potential Glycosyl Transferase Inhibitors by Thio‐Click Reactions

AbstractLeloir glycosyltransferases play an important role in many fundamental processes of living systems by catalyzing biological glycosylations. Neutral analogues of nucleotide sugars, as potential donor‐substrate inhibitors of Leloir glycosyltransferases, are of prime interest in medicinal chemistry. We report the development of S‐linked sugar‐nucleotide analogues by replacing the α‐O‐pyrophosphate bridge with an electroneutral ethyl or propyl linker by radical mediated hydrothiolation of 2‐substituted glycals and olefinic nucleoside analogues. UDP‐glucose and UDP‐GlcNAc analogues were assembled from 2‐substituted glycals, 1,2‐ethanedithiols and uridine 4’‐exomethylene derivative by two subsequent thio‐click reactions. Morpholino type mimetics of UDP‐, GDP‐ and CMP‐sugars were constructed by photoinitiated additions of 1‐thiosugars (Glc, GlcNAc, Gal, Man) and 2‐thio‐Neu5Ac onto N‐allyl morpholinos.

Modulating Properties of Piroxicam, Meloxicam and Oxicam Analogues against Macrophage-Associated Chemokines in Colorectal Cancer

The mechanisms underlying the antineoplastic effects of oxicams have not been fully elucidated. We aimed to assess the effect of classic and novel oxicams on the expression/secretion of macrophage-associated chemokines (RTqPCR/Luminex xMAP) in colorectal adenocarcinoma cells, and on the expression of upstream the non-steroidal anti-inflammatory drug (NSAID)-activated genes NAG1, NFKBIA, MYD88, and RELA, as well as at the chemokine profiling in colorectal tumors. Meloxicam downregulated CCL4 9.9-fold, but otherwise the classic oxicams had a negligible/non-significant effect. Novel analogues with a thiazine ring substituted with arylpiperazine and benzoyl moieties significantly modulated chemokine expression to varying degree, upregulated NAG1 and NFKBIA, and downregulated MYD88. They inhibited CCL3 and CCL4, and their effect on CCL2 and CXCL2 depended on the dose and exposure. The propylene linker between thiazine and piperazine nitrogens and one arylpiperazine fluorine substituent characterized the most effective analogue. Only CCL19 and CXCL2 were not upregulated in tumors, nor was CXCL2 in tumor-adjacent tissue compared to normal mucosa. Compared to adjacent tissue, CCL4 and CXCL2 were upregulated, while CCL2, CCL8, and CCL19 were downregulated in tumors. Tumor CCL2 and CCL7 increased along with advancing T and CCL3, and CCL4 along with the N stage. The introduction of arylpiperazine and benzoyl moieties into the oxicam scaffold yields effective modulators of chemokine expression, which act by upregulating NAG1 and interfering with NF-κB signaling.

Tethered Aryl Groups Increase the Activity of Anti-Proliferative Thieno[2,3-b]Pyridines by Targeting a Lipophilic Region in the Active Site of PI-PLC

The compounds 2-amino-3-carboxamido-thieno[2,3-b]pyridines have demonstrated excellent anti-proliferative activity against human cancer cell lines, including the triple-negative breast cancer cell line MDA-MB-231. In this study, 81 novel thieno[2,3-b]pyridines were synthesised in four series to further improve their anti-proliferative activity, in particular by targeting an adjacent lipophilic pocket in the putative target enzyme phosphoinositide phospholipase C (PI-PLC). Overall, it was found that appending a propyl-aryl group at C-5 on 2-amino-3-carboxamido-thieno[2,3-b]pyridine resulted in compounds with potent biological activity, exhibiting IC50 values in the nanomolar range. The propyl linker could be an α,β-unsaturated ketone or a saturated propyl ketone, but the highest activity was obtained when allylic alcohols were the tether between thieno[2,3-b]pyridine and the appended aryl group, with compound 21r having IC50 values lower than 50 nM. Compounds with one extra carbon in the tether (i.e., a four-atom chain) were found to be considerably less active. Molecular modelling revealed this propyl tether places the newly introduced aryl ring in an untargeted lipophilic pocket within the active site of the phosphoinositide phospholipase C (PI-PLC) enzyme.

Heat Shock Proteins HSPA1 and HSP90AA1 Are Upregulated in Colorectal Polyps and Can Be Targeted in Cancer Cells by Anti-Inflammatory Oxicams with Arylpiperazine Pharmacophore and Benzoyl Moiety Substitutions at Thiazine Ring.

Heat shock proteins HSPA1/Hsp70α and HSP90AA1/Hsp90α are crucial for cancer growth but their expression pattern in colorectal polyps or whether they can be modulated by oxicams is unknown. We quantified (RTqPCR) HSPA1 and HSP90AA1 expression in 50 polyp-normal pairs in relation to polyp malignancy potential and examined the effect of piroxicam, meloxicam and five novel analogues on HSPA1 and HSP90AA1 expression (mRNA/protein) in colorectal adenocarcinoma lines. HSPA1 and HSP90AA1 were upregulated in polyps by 3- and 2.9-fold. Expression ratios were higher in polyps with higher dysplasia grade and dominant villous growth pattern, mostly a result of diminished gene expression in normal tissue. Classic oxicams had negligible/non-significant effect on HSP expression. Their most effective analogue inhibited HSPA1 protein and gene by 2.5-fold and 5.7-fold in Caco-2 and by 11.5-fold and 6.8-fold in HCT116 and HSPA1 protein in HT-29 by 1.9-fold. It downregulated HSP90AA1 protein and gene by 1.9-fold and 3.7-fold in Caco-2 and by 2-fold and 5.0-fold in HCT116. HSPA1 and HSP90AA1 are upregulated in colorectal polyps reflecting their potential for malignancy. HSPA1 in cancer cells and, to lesser degree, HSP90AA1 can be reduced by oxicam analogues with thiazine ring substituted via propylene linker by arylpiperazine pharmacophore with fluorine substituents and by benzoyl moiety.

Does the Configuration at the Metal Matter in Noyori-Ikariya Type Asymmetric Transfer Hydrogenation Catalysts?

Noyori–Ikariya type [(arene)RuCl(TsDPEN)] (TsDPEN, sulfonated diphenyl ethylenediamine) complexes are widely used C=O and C=N reduction catalysts that produce chiral alcohols and amines via a key ruthenium–hydride intermediate that determines the stereochemistry of the product. Whereas many details about the interactions of the pro-chiral substrate with the hydride complex and the nature of the hydrogen transfer from the latter to the former have been investigated over the past 25 years, the role of the stereochemical configuration at the stereogenic ruthenium center in the catalysis has not been elucidated so far. Using operando FlowNMR spectroscopy and nuclear Overhauser effect spectroscopy, we show the existence of two diastereomeric hydride complexes under reaction conditions, assign their absolute configurations in solution, and monitor their interconversion during transfer hydrogenation catalysis. Configurational analysis and multifunctional density functional theory (DFT) calculations show the λ-(R,R)SRu configured [(mesitylene)RuH(TsDPEN)] complex to be both thermodynamically and kinetically favored over its λ-(R,R)RRu isomer with the opposite configuration at the metal. Computational analysis of both diastereomeric catalytic manifolds show the major λ-(R,R)SRu configured [(mesitylene)RuH(TsDPEN)] complex to dominate asymmetric ketone reduction catalysis with the minor λ-(R,R)RRu [(mesitylene)RuH(TsDPEN)] stereoisomer being both less active and less enantioselective. These findings also hold true for a tethered catalyst derivative with a propyl linker between the arene and TsDPEN ligands and thus show enantioselective transfer hydrogenation catalysis with Noyori–Ikariya complexes to proceed via a lock-and-key mechanism.

Preparation, structure and dimerization of molecular tweezer: Cyanuric acid core based flexible symmetric linked pthalimide moiety as a heteroaromatic system

Here, we synthesize tripodal tweezer molecule which have cyanuric acid in the center, propylene as a linker and pthalimide hetrocycle as terminal for conformational applications. The propylene linker promote intramolecular and intermolecular interactions within and encircle molecules. Appropriately, the geometrical specification set for the molecules which must be concert about conformations in different states. The conformational studies of this tripodal compound has been carried by X-ray crystallography. Evaluation of conformational stability in different conformation through theoretical calculations has been done.

Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation.

RG7388 (Idasanutlin) is a potent inhibitor of oncoprotein murine double minute 2 (MDM2). Herein we investigated the feasibility of developing 18F-labeled RG7388 as a radiotracer for imaging MDM2 expression in tumors with positron emission tomography (PET). Two fluorinated analogues of RG7388, 6 and 7, were synthesized by attaching a fluoronicotinyl moiety to RG7388 via a polyethylene glycol (PEG3) or a propyl linker. The inhibitory potency (IC50) of 6 and 7 against MDM2 was determined by a fluorescence polarization (FP)-based assay. Next, compound 6 was labeled with 18F using a trimethylammonium triflate precursor to obtain [18F]FN-PEG3-RG7388 ([18F]6), and its properties were evaluated in MDM2 expressing wild-type p53 tumor cell lines (SJSA-1 and HepG2) in vitro and in tumor xenografts in vivo. The FP assays revealed an IC50 against MDM2 of 119 nM and 160 nM for 6 and 7, respectively. 18F-labeling of 6 was achieved in 50.3 ± 7.5% radiochemical yield. [18F]6 exhibited a high uptake (∼70% of input dose) and specificity in SJSA-1 and HepG2 cell lines. Saturation binding assays revealed a binding affinity (Kd) of 128 nM for [18F]6 on SJSA-1 cells. In mice, [18F]6 showed fast clearance from blood with a maximum tumor uptake of 3.80 ± 0.85% injected dose per gram (ID/g) in HepG2 xenografts at 30 min postinjection (p.i.) and 1.32 ± 0.32% ID/g in SJSA-1 xenografts at 1 h p.i. Specificity of [18F]6 uptake in tumors was demonstrated by pretreatment of mice with SJSA-xenografts with a blocking dose of RG7388 (35 mg/kg body weight, i.p.). In vivo stability studies in mice using HPLC showed ∼60% and ∼30% intact [18F]6 remaining in plasma at 30 min and 1 h p.i., respectively, with the remaining activity attributed to polar peaks. Our results suggest that RG7388 is a promising molecular scaffold for 18F-labeled probe development for MDM2. Additional labeling strategies and functionalizing locations on RG7388 are under development to improve binding affinity and in vivo stability of the 18F-labeled compound to make it more amenable for PET imaging of MDM2 in vivo.