Formal [4+3] Epoxide Cascade Reaction via a Complementary Ambiphilic Pairing Strategy

A formal [4+3] epoxide cascade protocol utilizing ambiphilic sulfonamides and a variety of epoxides (masked ambiphiles) has been developed for the generation of benzothiaoxazepine-1,1′-dioxides and oxathiazepine-1,1′-dioxides. This protocol combines an epoxide ring-opening with either an SNAr or oxa-Michael cyclization pathway

ROMP-derived Oligomeric Phosphates for Application in Facile Benzylation

The development of new ROMP-based oligomeric benzyl phosphates (OBPn) is reported for use as soluble, stable benzylating reagents. These oligomeric reagents are readily synthesized from commercially available materials and conveniently polymerized and purified in a one-pot process, affording bench stable, pure white, free-flowing solids on multi-gram scale. Utilization in benzylation reactions with a variety of nucleophiles is reported

A Formal [4+4] Complementary Ambiphile Pairing (CAP) Reaction: A New Cyclization Pathway for ortho-Quinone Methides

A formal, one-pot, [4+4] cyclization pathway for the generation of 8-member sultams via in-situ generation of an ortho-quinone methide (o-QM) is reported. The pairing of ambiphilic synthons in a complementary fashion is examined whereby o-fluorobenzenesulfonamides are merged with in-situ-generated o-QM in a formal [4+4] cyclization pathway to afford 5,2,1-dibenzooxathiazocine-2,2-dioxide scaffolds under microwave (mW) conditions. The method reported represents the first use of an o-QM in a formal hetero [4+4] cyclization

Synthesis, Characterization and Remarkable Anticancer Activity of Rhenium Complexes Containing Biphenyl Appended NNN Donor Sulfonamide Ligands

Neutral and cationic rhenium complexes provide both hydrophilic as well as hydrophobic properties due to the robustness of the tridentate ligand system of biphenyl appended dipicolylamine (N(SO2bip)dpa) and diethylenetriamine (N(SO2bip)dienH) coordinated to the [Re(CO)3]+ core, hold immense potential for the development of metal based anticancer drugs. This was achieved by the synthesis of two ligands (L1: N(SO2bip)dpa and L2: (N(SO2bip)dienH) and their corresponding Re complexes (C1: [Re(CO)3(N(SO2bip)dpa)]PF6 and C2: [Re(CO)3(N(SO2bip)dien)] in good yield and high purity. All four compounds were characterized by 1H NMR, UV-Vis, FTIR spectroscopies and L1, also by single crystal X-ray diffraction. The methylene protons observed as a singlet at (4.59 ppm) in a 1H NMR spectrum of L1 appear as two doublets (5.66 and 4.65 ppm) in the spectrum of C1. The appearance of NH signals at 3.48, 5.17 and 6.69 ppm in the 1H NMR spectrum of C2 confirm the coordination of L2 with Re. The stretching vibration frequencies depicted by the S-N bond at 923 cm-1 for L1 appear towards lower frequencies (821 cm-1) in an FTIR spectrum of C1, while the S-N bond at 943 cm-1 for L2 appears towards higher frequencies (968 cm-1) in C2. In silico assessment of drug likeliness revealed zero violations demonstrating a high likeliness of the ligands to be successful as drug leads. All four compounds have shown very low IC50 values against non-small cell lung cancer cells (NCI-H292). Therefore, L1, C1, L2 and C2 are promising novel compounds that can be further investigated as potential anticancer agents. Keywords: Rhenium Tricarbonyl, Sulfonamide, Anticancer, Fluorescence

Accessing Stereochemically Rich Sultams via Microwave-Assisted, Continuous Flow Organic Synthesis (MACOS) Scale-out

The generation of stereochemically-rich benzothiaoxazepine-1,1′-dioxides for enrichment of high-throughput screening collections is reported. Utilizing a microwave-assisted, continuous flow organic synthesis platform (MACOS), scale-out of core benzothiaoxazepine-1,1′-dioxide scaffolds has been achieved on multi-gram scale using an epoxide opening/SNAr cyclization protocol. Diversification of these sultam scaffolds was attained via a microwave-assisted intermolecular SNAr reaction with a variety of amines. Overall, a facile, 2-step protocol generated a collection of benzothiaoxazepine-1,1′-dioxides possessing stereochemical complexity in rapid fashion, where all 8 stereoisomers were accessed from commercially available starting materials

Screening of five Sri Lankan endemic plants for anti-cancer effects on breast cancer stem cells isolated from MCF-7 and MDA-MB-231 cell lines

Purpose: To screen selected endemic plants grown in Sri Lanka on breast cancer stem cells (bCSCs) for their anti-cancer propertiesMethods: Breast-CSCs expressing CD24-/CD44+ surface markers were isolated from MDA-MB-231 cells by magnetic-assisted cell sorting method and validated using flow cytometry. A panel of forty extracts from barks and leaves of Doona nervosa, Garcinia quaesita, Garcinia zeylanica, Memecylon rostratum and Schumacheria castaneifolia were obtained by sequential solvent extraction and tested on bCSC-mammospheres derived from MDA-MB-231 and MCF-7 cells and normal mammary epithelial (MCF-10A) cells. Proliferation and cell stemness were analyzed using WST-1 cell proliferation assay and alkaline phosphatase assay.Results: Hexane and chloroform extracts of G. zeylanica and G. quaesita barks showed dosedependent reduction in proliferation and stemness in both bCSCs tested with less effect on MCF-10A cells. Hexane, chloroform and ethyl acetate extracts of S. castaneifolia bark selectively inhibited mammospheres of triple negative bCSCs cells.Conclusion: This study demonstrates that the non-polar extracts of G. zeylanica and G. quaesita, S. castaneifolia barks inhibit the proliferation of bCSCs of triple negative and estrogen-progesterone positive breast cancers. Findings of the present study may useful for developing a future anti-cancer therapeutics which can target bCSCs.Keywords: Cancer stem cells, Garcinia zeylanica, Garcinia quaesita, Schumacheria castaneifolia, Mammosphere

Redox-Induced Src Kinase and Caveolin-1 Signaling in TGF-β1-Initiated SMAD2/3 Activation and PAI-1 Expression

Plasminogen activator inhibitor-1 (PAI-1), a major regulator of the plasmin-based pericellular proteolytic cascade, is significantly increased in human arterial plaques contributing to vessel fibrosis, arteriosclerosis and thrombosis, particularly in the context of elevated tissue TGF-β1. Identification of molecular events underlying to PAI-1 induction in response to TGF-β1 may yield novel targets for the therapy of cardiovascular disease.Reactive oxygen species are generated within 5 minutes after addition of TGF-β1 to quiescent vascular smooth muscle cells (VSMCs) resulting in pp60(c-src) activation and PAI-1 expression. TGF-β1-stimulated Src kinase signaling sustained the duration (but not the initiation) of SMAD3 phosphorylation in VSMC by reducing the levels of PPM1A, a recently identified C-terminal SMAD2/3 phosphatase, thereby maintaining SMAD2/3 in an active state with retention of PAI-1 transcription. The markedly increased PPM1A levels in triple Src kinase (c-Src, Yes, Fyn)-null fibroblasts are consistent with reductions in both SMAD3 phosphorylation and PAI-1 expression in response to TGF-β1 compared to wild-type cells. Activation of the Rho-ROCK pathway was mediated by Src kinases and required for PAI-1 induction in TGF-β1-stimulated VSMCs. Inhibition of Rho-ROCK signaling blocked the TGF-β1-mediated decrease in nuclear PPM1A content and effectively attenuated PAI-1 expression. TGF-β1-induced PAI-1 expression was undetectable in caveolin-1-null cells, correlating with the reduced Rho-GTP loading and SMAD2/3 phosphorylation evident in TGF-β1-treated caveolin-1-deficient cells relative to their wild-type counterparts. Src kinases, moreover, were critical upstream effectors of caveolin-1(Y14) phosphoryation and initiation of downstream signaling.TGF-β1-initiated Src-dependent caveolin-1(Y14) phosphorylation is a critical event in Rho-ROCK-mediated suppression of nuclear PPM1A levels maintaining, thereby, SMAD2/3-dependent transcription of the PAI-1 gene

Rapid, Scalable Assembly of Stereochemically Rich, Mono- and Bicyclic Acyl Sultams

A one-pot, sequential protocol is reported that involves complementary ambiphile pairing (CAP) of a vinyl sulfonamide with a variety of unprotected amino acids via aza-Michael addition and subsequent intramolecular amidation. The method generates diverse, sp3-rich mono- and bicyclic acyl sultams in a highly scalable manner. Modular pairing of stereochemically rich building blocks allows quick access to all possible isomers. Extension to include one-pot, sequential 3-, 4- and 5-multicomponent protocols is also discussed

Scaling Out by Microwave-Assisted, Continuous Flow Organic Synthesis (MACOS): Multi-Gram Synthesis of Bromo- and Fluoro-benzofused Sultams Benzthiaoxazepine-1,1-dioxides

This is the peer reviewed version of the following article: Ullah, F., Samarakoon, T., Rolfe, A., Kurtz, R. D., Hanson, P. R., & Organ, M. G. (2010). Scaling Out by Microwave-Assisted, Continuous Flow Organic Synthesis (MACOS): Multi-Gram Synthesis of Bromo- and Fluoro-benzofused Sultams Benzthiaoxazepine-1,1-dioxides. Chemistry (Weinheim an Der Bergstrasse, Germany), 16(36), 10959–10962. http://doi.org/10.1002/chem.201001651, which has been published in final form at doi.org/10.1002/chem.201001651. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving