Studies on carbo- and amino functionalization of alkenes by conjugate addition and hydroamination

This dissertation describes studies on carbo- and amino-functionalization of alkenes using conjugate addition and hydroamination strategy. In Chapter 1, the importance and chemical functionalization of alkenes are highlighted in Chapter 1. Chapter 2 describes development of a methodology that employs organic diamine as catalyst for conjugate addition reactions of active methine nucleophiles to acrylate derivatives. It could be speculated that hydrogen bonding plays a vital role to activate the less reactive acrylate derivatives towards conjugate addition. Chapter 3 entails a domino SN2-conjugate addition sequence for the diastereoselective synthesis of various carbocyclic compounds. The strategy is applied for synthesis of bicyclic lactone derivatives including biologically active natural products, dihydronepatalactone, isodihydronepetalactone and 1-epi-isodihydronepetalactone. Chapter 4 describes a method for synthesis of cyclic nitrones using alkenyl oximes based on inorganic base-mediated hydroamination. DFT calculations of the reaction pathway suggested that the present hydroamination could proceed via unprecedented nucleophilic amination of unactivated alkene by the oxime nitrogen, the transition state of which is stabilized by ionic interaction of the metal cation such as K+ on the oxime oxygen and negatively charged alkene moiety.DOCTOR OF PHILOSOPHY (SPMS

Formal [4 + 1]- and [5 + 1]-annulation by an SN2–conjugate addition sequence : stereoselective synthesis of highly substituted carbocycles

K2CO3-mediated reactions of 6-bromo-2-hexenoates and 7-bromo-2-heptenoate with active methylene compounds deliver highly substituted cyclopentane and cyclohexane derivatives, respectively via a sequence of SN2–conjugate addition reactions (formal [4 + 1]- and [5 + 1]-annulation) in a diastereoselective manner

Formal [4 + 1]- and [5 + 1]-Annulation by an S_N2–Conjugate Addition Sequence: Stereoselective Synthesis of Highly Substituted Carbocycles

K₂CO₃-mediated reactions of 6-bromo-2-hexenoates and 7-bromo-2-heptenoate with active methylene compounds deliver highly substituted cyclopentane and cyclohexane derivatives, respectively via a sequence of S_N2–conjugate addition reactions (formal [4 + 1]- and [5 + 1]-annulation) in a diastereoselective manner

Formal [4 + 1]- and [5 + 1]-Annulation by an S_N2–Conjugate Addition Sequence: Stereoselective Synthesis of Highly Substituted Carbocyles

Formal [4 + 1]- and [5 + 1]-Annulation by an S_N2–Conjugate Addition Sequence: Stereoselective Synthesis of Highly Substituted Carbocyle

Formal [4 + 1]- and [5 + 1]-Annulation by an S_N2–Conjugate Addition Sequence: Stereoselective Synthesis of Highly Substituted Carbocycles

K₂CO₃-mediated reactions of 6-bromo-2-hexenoates and 7-bromo-2-heptenoate with active methylene compounds deliver highly substituted cyclopentane and cyclohexane derivatives, respectively via a sequence of S_N2–conjugate addition reactions (formal [4 + 1]- and [5 + 1]-annulation) in a diastereoselective manner

Formal [4 + 1]- and [5 + 1]-Annulation by an S_N2–Conjugate Addition Sequence: Stereoselective Synthesis of Highly Substituted Carbocycles

K₂CO₃-mediated reactions of 6-bromo-2-hexenoates and 7-bromo-2-heptenoate with active methylene compounds deliver highly substituted cyclopentane and cyclohexane derivatives, respectively via a sequence of S_N2–conjugate addition reactions (formal [4 + 1]- and [5 + 1]-annulation) in a diastereoselective manner

Formal [4 + 1]- and [5 + 1]-Annulation by an S_N2–Conjugate Addition Sequence: Stereoselective Synthesis of Highly Substituted Carbocycles

K₂CO₃-mediated reactions of 6-bromo-2-hexenoates and 7-bromo-2-heptenoate with active methylene compounds deliver highly substituted cyclopentane and cyclohexane derivatives, respectively via a sequence of S_N2–conjugate addition reactions (formal [4 + 1]- and [5 + 1]-annulation) in a diastereoselective manner

Nox4-dependent ROS modulation by amino endoperoxides to induce apoptosis in cancer cells

Tumor metastasis is the main cause of death in cancer patients. Anoikis resistance is one critical malefactor of metastatic cancer cells to resist current clinical chemotherapeutic treatments. Although endoperoxide-containing compounds have long been suggested as anticancer drugs, few have been clinically employed due to their instability, complex synthesis procedure or low tumor cell selectivity. Herein, we describe a one-pot strategy to synthesize novel amino endoperoxides and their derivatives with good yields and stabilities. In vitro cell-based assays revealed that 4 out of the 14 amino endoperoxides selectively induce metastatic breast carcinoma cells but not normal breast cells to undergo apoptosis, in a dose-dependent manner. Mechanistic studies showed that the most potent amino endoperoxide, 4-Me, is selective for cancer cells expressing a high level of Nox4. The anticancer effects are further shown to be associated with reduced O2−:H2O2 ratio and increased ·OH level in the cancerous cells. Animal study showed that 4-Me impairs orthotopic breast tumor growth as well as tumor cell metastasis to lymph nodes. Altogether, our study suggests that anticancer strategies that focus on redox-based apoptosis induction in tumors are clinically viable.Published versio

Early controlled release of peroxisome proliferator-activated receptor β/δ agonist GW501516 improves diabetic wound healing through redox modulation of wound microenvironment

Diabetic wounds are imbued with an early excessive and protracted reactive oxygen species production. Despite the studies supporting PPARβ/δ as a valuable pharmacologic wound-healing target, the therapeutic potential of PPARβ/δ agonist GW501516 (GW) as a wound healing drug was never investigated. Using topical application of polymer-encapsulated GW, we revealed that different drug release profiles can significantly influence the therapeutic efficacy of GW and consequently diabetic wound closure. We showed that double-layer encapsulated GW microparticles (PLLA:PLGA:GW) provided an earlier and sustained dose of GW to the wound and reduced the oxidative wound microenvironment to accelerate healing, in contrast to single-layered PLLA:GW microparticles. The underlying mechanism involved an early GW-mediated activation of PPARβ/δ that stimulated GPx1 and catalase expression in fibroblasts. GPx1 and catalase scavenged excessive H2O2 accumulation in diabetic wound beds, prevented H2O2-induced ECM modification and facilitated keratinocyte migration. The microparticles with early and sustained rate of GW release had better therapeutic wound healing activity. The present study underscores the importance of drug release kinetics on the therapeutic efficacy of the drug and warrants investigations to better appreciate the full potential of controlled drug release.Accepted versio