ADME/PK Insights of Crocetin: A Molecule Having an Unusual Chemical Structure with Druglike Features.

Crocetin is a promising phyto-based molecule to treat Alzheimer's disease (AD). The chemical structure of crocetin is incongruent with various standard structural features of CNS drugs. As poor pharmacokinetic behavior is the major hurdle for any candidate to become a drug, we elucidated its druggable characteristics by implementing in silico, in vitro, and in vivo approaches, as limited ADME/PK information is available. Results demonstrate several attributes of crocetin based on rules of drug-likeness, lipophilicity, pKa, P-gp inhibitory activity, plasma stability, RBC partitioning, metabolic stability, CYP inhibitory action, blood-brain barrier (BBB) permeability, oral bioavailability, and pharmacokinetic interaction with marketed anti-Alzheimer's drugs (memantine, donepezil, galantamine, and rivastigmine). However, aqueous solubility, chemical stability, plasma protein binding, and P-gp induction are some concerns associated with this molecule that should be taken into consideration during its further development. Overall results indicate favorable ADME/PK behavior and potential druggable candidature of crocetin.

Diastereoselective synthesis of functionalized spiroindolines via intramolecular ipso-iodocyclization/nucleophile addition cascade reactions of indole-tethered ynones.

Herein, we describe a highly diastereoselective approach for synthesizing polyfunctionalized spiroindolines from indolyl-ynones involving an ipso-iodocyclization/nucleophile addition cascade. The developed strategy allows the formation of a spirocyclic core and the installation of two functional groups in a single operation. Also this strategy is accompanied by the generation of two C-C and one C-I bonds and two contiguous stereocenters.

Ag(I)-catalyzed dearomatizing spirocyclization/nucleophile addition cascade reactions of indole-tethered ynones.

Ag(I)-catalyzed highly diastereoselective construction of divergent spiroindolines is disclosed herein. The approach proceeds via dearomatizing spirocyclization of indole-tethered ynones followed by C-nucleophile or hydride trapping. The established strategy is accompanied by the generation of two new C-C bonds and two contiguous stereocenters. This strategy features a broad range of (hetero)arenes as C-nucleophiles and excellent diastereoselectivity.

Sulfonylpyrazole- and pyrazole-directed ortho-selective C-H functionalization/alkenylation and desulfenylative olefination of aryl(sulfonyl)pyrazoles.

ortho-Selective C-H alkenylation of arenes was achieved using sulfonylpyrazoles and pyrazoles as directing groups, favored by a combination of a Pd(OAc)2 catalyst, Boc-Sar-OH and silver acetate. A wide variety of mono-alkenylated products of aryl-sulfonylpyrazoles and pyrazoles were synthesized with complete site-selectivity under mild reaction conditions. This transformation tolerated several electron-withdrawing and electron-donating groups on the aryl ring and the yields ranged from 52% to 70%, producing highly decorated/valuable alkenylated sulfonylpyrazole and pyrazole derivatives. Amazingly, switching of the oxidant, with the use of AgBF4 in place of AgOAc, offered cinnamic acid derivatives through de-sulfonylation followed by alkenylation at the same position with good yields in the case of aryl-sulfonylpyrazoles. These kinds of molecules have great biological importance and target predictions indicate that they may serve as potential antifungal and anti-tumor agents.

Ellagic Acid Exerts Dual Action to Curb the Pathophysiological Manifestations of Sickle Cell Disease and Attenuate the Hydroxyurea-Induced Myelosuppression in Berkeley Mice.

The use of adjuvant therapy is an attractive approach to manage sickle cell disease (SCD) symptomatically. The present study aimed to investigate the potential of ellagic acid as an adjuvant therapy with hydroxyurea (HU), a key drug for SCD with myelosuppressive toxic effects. A panel of experiments was performed using SCD patient's blood (ex vivo) and transgenic mice model of SCD (in vivo). Ellagic acid exhibited the following beneficial pharmacological actions: (a) potent anti-sickling, polymerization inhibitory, and inherent non-hemolytic activity; (b) pronounced action to abrogate HU-induced neutropenia and to improve key hematological parameters during SCD (RBC, Hb, platelet levels); (c) considerable action to foster vascular tone (L-proline); (d) marked attenuating effect against oxidative stress (nitrotyrosine, hypoxanthine, MDA, GSH); (e) substantial inhibitory role against inflammation (analgesic activity and regulation of hemin, TNF-α, IL-1ß, NF-κB/IκBα); (f) remarkable outcome of declining vaso-occlusive crisis (P-selectin, ERK1/2); (g) notable shielding deed against elevated biochemical marker for organ toxicity (creatinine); (h) noticeably prevented histopathological alterations of the spleen. Additionally, the pharmacokinetic study results of HU in the presence and absence of ellagic acid using a mouse model demonstrate that ellagic acid could be safely co-administered with HU. Overall findings suggest that ellagic acid is a promising candidate for adjuvant therapy in SCD based on its own significant ability against SCD and potentiating capability of HU action via targeting improvement at the various stages of pathophysiological complications during SCD and minimizing HU-induced toxicological manifestations.

Discovery of SDS-347 as a specific peptide competitive inhibitor of G9a with promising anti-cancer potential.

BACKGROUND: G9a is a histone H3K9 methyltransferase enzyme found highly upregulated in many cancers. H3 binds to the rigid I-SET domain and the cofactor, S-adenosyl methionine, binds to the flexible post-SET domain of G9a. Inhibition of G9a is known to inhibit the growth of cancer cell-lines. METHODS: Recombinant G9a and H3 were used to develop radioisotope-based inhibitor screening assay. The identified inhibitor was evaluated for isoform selectivity. The mode of enzymatic inhibition was studied by enzymatic assays and bioinformatics. Anti-proliferative activity of the inhibitor was studied in cancer cell lines by utilizing MTT assay. The mechanism of cell death was studied by western blotting and microscopy. RESULTS: We developed a robust G9a inhibitor screening assay that led to the discovery of SDS-347 as a potent G9a inhibitor with IC50 of 3.06 µM. It was shown to reduce the levels of H3K9me2 in cell-based assay. The inhibitor was found to be peptide competitive and highly specific as it did not show any significant inhibition of other histone methyltransferases and DNA methyltransferase. Docking studies showed that SDS-347 could form direct bonding interaction with Asp1088 of the peptide-binding site. SDS-347 showed anti-proliferative effect against various cancer cell lines especially the K562 cells. Our data suggested that SDS-347 mediated antiproliferative action via ROS generation, induction of autophagy and apoptosis. CONCLUSION: Overall, the findings of the current study include development of a new G9a inhibitor screening assay and identification of SDS-347, as a novel, peptide competitive and highly specific G9a inhibitor with promising anticancer potential.

Flurbiprofen inhibits heme induced NLRP3 inflammasome in Berkeley sickle cell disease mice.

Sickle cell disease (SCD) is accompanied by several complications, which emanate from the sickling of erythrocytes due to a point mutation in the ß-globin chain of hemoglobin. Sickled erythrocytes are unable to move smoothly through small blood capillaries and therefore, cause vaso occlusion and severe pain. Apart from pain, continuous lysis of fragile sickled erythrocytes leads to the release of heme, which is a strong activator of the NLRP3 inflammasome, thus producing chronic inflammation in sickle cell disease. In this study, we identified flurbiprofen among other COX-2 inhibitors to be a potent inhibitor of heme-induced NLRP3 inflammasome. We found that apart from being a nociceptive agent, flurbiprofen exerts a strong anti-inflammatory effect by suppressing NF-κB signaling, which was evidenced by reduced levels of TNF-α and IL-6 in wild-type and sickle cell disease Berkeley mice models. Our data further demonstrated the protective effect of flurbiprofen on liver, lungs, and spleen in Berkeley mice. The current sickle cell disease pain management regime relies mainly on opiate drugs, which is accompanied by several side effects without modifying the sickle cell disease-related pathology. Considering the potent role of flurbiprofen in inhibiting NLRP3 inflammasome and other inflammatory cytokines in sickle cell disease, our data suggests that it can be explored further for better sickle cell disease pain management along with the possibility of disease modification.

Pyrazolopyrimidinone Based Selective Inhibitors of PDE5 for the Treatment of Erectile Dysfunction.

Continuing research with our earlier finding of sildenafil based analogs in the search of new inhibitors of PDE5 for erectile dysfunction suggested that there is a scope of modifications at N-methylpiperazine ring with hydrophobic region followed by hydrogen bond donor or acceptor region. However, the leads identified earlier had some limitations like poor pharmacokinetic (PK) profile, low aqueous solubility and poor bioavailability. In this direction, a new series of sildenafil based analogs were designed, synthesized and screened for their PDE5 inhibitory activity. In this series compound 18 was found to have excellent in vitro activity with selectivity towards PDE5 isozyme, also the in vivo activity and pharmacokinetic profile was excellent. The cyp inhibition and CaCO2 permeability was also excellent for compound 18.

Iodocycloisomerization/Nucleophile Addition Cascade Transformations of 1,2-Alkynediones.

A general electrophilic iodocyclization/nucleophile addition cascade transformation for 1,2-alkynediones for the synthesis of various oxygen heterocycles and access to regioselective alkyne hydroxylation is reported. Furan-tethered ynediones resulted in the construction of exo-enol ethers via carbonyl-alkyne cyclization-initiated heteroarene dearomatization, whereas other (hetero)arene-, alkenyl-, and alkyl-tethered ynediones resulted in the formation of highly functionalized 3(2H)-furanones. Importantly, the developed domino protocols involve the construction of important heterocyclic scaffolds and installation of two functional groups in a single operation. Moreover, the use of water as a nucleophile resulted in regioselective alkyne hydroxylation via furanone ring opening. The developed protocols are characterized by a wide substrate scope, and their utility has been demonstrated by a number of postsynthetic transformations.

TBAX/Oxone-Mediated Halogenation of Pyrazoles and Other Heterocycles: An Entry to Important Cross-Coupling Reactions.

A facile, sustainable and eco-friendly protocol has been developed for the halogenation of various heterocycles using TBAX (TBAI/TBAB/TBACl) as halogenating agent, which afforded the products in 90-95% isolated yields. The reaction proceeds with low-cost TBAX and uses greener conditions like EtOH as a solvent and microwave as an alternative energy source for reaction. This protocol has been applied on pyrazoles and extended to different heterocycles like 7-azaindole, indazole, indole and 2-phenylimidazo[1,2-α]pyridines. The gram-scale iodination reaction has also been successfully performed by optimizing conventional heating conditions, which demonstrates its potential applicability in organic synthesis. Further these halogenated pyrazoles have been utilized for different coupling reactions including formation of arylated, alkynylated and sulfenated pyrazoles. However, TBAF mediated fluorination did not work.

Visible-light-promoted iron-catalyzed C-H functionalization of 1,4-naphthoquinones via oxidative coupling with sulfoximines.

A catalytic oxidative addition of sulfoximines to naphthoquinones via C-H functionalization has been achieved using an iron catalytic system, which exhibits good reactivity and high regioselectivity in the presence of visible light. This is the first report offering an efficient protocol for obtaining (naphtho)quinone-sulfoximine hybrid analogs in moderate to good yields with wide scope for both the substrates. This protocol has also been applied on natural products for their modification, including vitamin K3, Juglone and some other modified natural scaffolds as well.

Iodine/TBHP-Mediated One-Pot Multicomponent Protocol for Tandem C-N and C-S Bond Formation To Access Sulfenylimidazo[1,5-a]pyridines via C-H Functionalization.

A mild and simple protocol has been established for the formation of sulfenylated imidazo[1,5-a]pyridines. This is a metal-free iodine/TBHP-mediated one-pot multicomponent reaction, which follows C-H functionalization of the imidazo[1,5-a]pyridine skeleton formed during the reaction and its subsequent sulfenylation in the same step to offer sulfenylated imidazo[1,5-a]pyridines in good to high yields. The extension and applications of this method have also been demonstrated.

Gold(I)-Catalyzed Cycloisomerization-Indole Addition Cascade: Synthesis of 3(2H)-Furanone-Incorporated Unsymmetrical 3,3'- Bis(indolyl)methanes.

An unprecedented Au(I)-catalyzed domino intramolecular carbonyl-alkyne cyclization/indole addition strategy has been disclosed here. This generalized strategy enables the synthesis of 3(2H)-furanone-incorporated unsymmetrical bis(indolyl)methanes with generation of a stereocenter at the furanone junction from easily accessible indole-tethered ynediones. In addition, this present protocol could also be extended for the synthesis of a number of indolyl-(hetero)arylmethanes by employing a variety of (hetero)arenes as a nucleophile coupling partner.

Selective Synthesis of Bis-Heterocycles via Mono- and Di-Selenylation of Pyrazoles and Other Heteroarenes.

The insertion of selenium was achieved in the form of mono-selenides and di-selenides for the preparation of novel bis-heterocyclic compounds. This method is more general and provides scaffold diversity with high yields of products. The concentration-dependent mono- and di-selenylation reaction selectivity was achieved using SeO2 as an efficient selenylating reagent.

Activation of lysosomal mediated cell death in the course of autophagy by mTORC1 inhibitor.

Lysosomal biogenesis plays a vital role in cell fate. Under certain conditions, excessive lysosomal biogenesis leads to susceptibility for lysosomal membrane permeabilization resulting in various pathological conditions including cell death. In cancer cells apoptosis machinery becomes dysregulated during the course of treatment, thus allows cancer cells to escape apoptosis. So it is therefore imperative to identify cytotoxic agents that exploit non-apoptotic mechanisms of cell death. Our study showed that pancreatic cancer cells treated with SDS-203 triggered an incomplete autophagic response and a nuclear translocation of transcriptional factor TFEB. This resulted in abundant biosynthesis and accumulation of autophagosomes and lysosomes into the cells leading to their death. It was observed that the silencing of autophagy genes didn't alter the cell fate, whereas siRNA-mediated silencing of TFEB subdued SDS-203 mediated lysosomal biogenesis and associated cell death. Further mouse tumors treated with SDS-203 showed a significant reduction in tumor burden and increased expression of lysosomal markers. Taken together this study demonstrates that SDS-203 treatment triggers non-apoptotic cell death in pancreatic cancer cells through a mechanism of lysosome over accumulation.

Mechanistic investigation of synergistic interaction of tocopherol succinate with a quinoline-based inhibitor of mammalian target of rapamycin.

OBJECTIVES: Cancer monotherapy is associated with various limitations; therefore, combination chemotherapy is widely explored for optimum drug efficacy. In this study, 4-(N-Phenyl-N'-substituted benzenesulfonyl)-6-(4-hydroxyphenyl) quinoline-based mammalian target of rapamycin (mTOR) inhibitor (IIIM-4Q) was investigated in combination with tocopherol succinate (TOS), and the mechanism of cytotoxicity was elucidated. METHODS: The cytotoxic potential of IIIM-4Q and TOS was evaluated in five cell lines. Further, to understand the mechanism of cytotoxicity of IIIM-4Q, TOS and their combination, various studies including morphological analysis using scanning electron microscopy and 6-diamidino-2-phenylindole (DAPI) staining, estimation of reactive oxygen species (ROS) level, measurement of mitochondrial membrane potential (MMP), in-vitro cell migration assay, Western blotting and staining with acridine orange (AO) for autophagy detection were performed. KEY FINDINGS: Investigated combination was synergistic in nature and exhibited greater oxidative stress and mitochondrial dysfunction in pancreatic cancer cells. The migration potential of MIA PaCa-2 cells was significantly mitigated under the influence of this combination, and morphological changes such as chromatin condensation and nuclear blebbing were observed. Also, poly (adenosine diphosphate-ribose) polymerase cleavage and caspase-3 activation were observed in IIIM-4Q and TOS combination-treated cells. CONCLUSIONS: The investigated combination synergistically inhibited proliferation of MIA PaCa-2 cells through simultaneous induction of autophagy followed by apoptosis, and this combination demonstrated potential for further translational studies.

Heteroarene-tethered Functionalized Alkyne Metamorphosis.

Heteroarene-tethered functionalized alkynes are multipotent synthons in organic chemistry. This detailed Review described herein offers a thorough discussion of the metamorphosis of heteroarene-tethered functionalized alkynes, an area which has earned much attention over the past decade in the straightforward synthesis of architecturally complex heterocyclic scaffolds in atom and step economic manner. Depending upon the variety of functionalized alkynes, this Review is divided into multiple sections. Amongst the vast array of synthetic transformations covered, dearomatizing spirocyclizations and cascade spirocyclization/rearrangement are of great interest. Synthetic transformations involving the heteroarene-tethered functionalized alkynes with scope, challenges, limitations, mechanism, their application in the total synthesis of natural products and future perceptions are surveyed.

Photo-induced 1,2-carbohalofunctionalization of C-C multiple bonds via ATRA pathway.

Radical vicinal carbohalofunctionalization of C-C multiple bonds via atom transfer processes constitutes an efficient method for the construction of halogenated building blocks with complete atom economy via radical cleavage of a pre-existing carbon-halogen σ-bond of an atom transfer reagent and their transposition over the π-bond of alkenes and alkynes. This review summarizes the recent advances in the photo-induced version of this class of transformations. A variety of transition-metal complexes, organic dyes, phosphines, amines, phenols and aldehydes were utilized as catalysts for the cleavage of the existing carbon-halogen bond of the corresponding atom transfer reagent in the presence of a light source. Alongside a variety of 1,2-haloalkylation and haloperfluoroalkylation reactions, atom transfer radical addition (ATRA) or cyclization (ATRC) reactions via the cleavage of the carbon-halogen bonds of aryl halides are also discussed.

Chiral Transient Directing Group Strategies in Asymmetric Synthesis.

The development of novel methodologies for catalytic enantioselective functionalization reactions enabled by chiral transient directing groups is accompanying in a paradigm shift in the field of asymmetric synthesis. In particular, these highly atom- and step-economic enantioinduction processes commonly proceed either via enantioselective C-H functionalization, or via enantioselective hydroarylation of the pro-chiral substrates generating point, axial or planar chirality. The use of the transient directing group strategy in C-H functionalizations precludes the stoichiometric installations and removal of directing groups and enables efficient, more compatible and economical chemical routes. This minireview highlights asymmetric transition-metal-catalyzed methodologies involving chiral transient directing groups together with the scope, utility and future perspective of the field.