Nagaraju Mupparapu

Metal-Free Oxidative Amidation of 2-Oxoaldehydes: A Facile Access to α-Ketoamides

A novel and efficient method for the synthesis of α-ketoamides, employing a dimethyl sulfoxide (DMSO)-promoted oxidative amidation reaction between 2-oxoaldehydes and amines under metal-free conditions is presented. Furthermore, mechanistic studies supported an iminium ion-based intermediate as a central feature of reaction wherein C1-oxygen atom of α-ketoamides is finally derived from DMSO.

Aminocatalytic Cross‐Coupling Approach via Iminium Ions to Different CC Bonds

Given the attractive ability of iminium ions to functionalize molecules directly at ostensibly unreactive positions, the reactivity of iminium ions, in which an α CH2 group is replaced by CO was explored. Background studies on the ability of such iminium cations to promote reactions via an iminium-catalyzed or iminium-equivalent pathway are apparently unavailable. Previously, tandem cross-coupling reactions were reported, in which an iminium ion undergoes nucleophilic 1,2-addition to give a putative three-component intermediate that abstracts a proton in situ and undergoes self-deamination followed by unprecedented DMSO/aerobic oxidation to generate α-ketoamides. However, later it was observed that iminium ions can generate valuable α-ketoamides through simple aerobic oxidation. In all reactions, iminium ions were generated in situ by reaction of 2-oxoaldehydes with secondary amines.

Unexplored reactivity of 2-oxoaldehydes towards Pictet–Spengler conditions: concise approach to β-carboline based marine natural products

Novel reactions under Pictet–Spengler conditions between tryptophan methyl ester/tryptamine and 2-oxoaldehydes have been developed and successfully utilized for the total synthesis of Merinacarboline (A and B), Eudistomin Y1, Pityriacitrin B, Pityriacitrin, Fascaplysin and analogues.

Amino Catalytic Oxidative Thioesterification Approach to α-Ketothioesters.

An efficient metal-free method for the synthesis of α-ketothioesters is described for the first time. This reaction features the ability of pyrrolidine to fine-tune the reaction between 2-oxoaldehyde and thiols through iminium to the desired product in moderate to good yields. As an advantage, no external oxidants or metal catalysts are required in our method. Reactions performed under modified conditions lead to an apparent balance in reactivity of secondary amine and thiols toward 2-oxoaldehydes.

Modulation of glycolysis and lipogenesis by novel PI3K selective molecule represses tumor angiogenesis and decreases colorectal cancer growth.

Phosphatidylinositol 3-kinase (PI3K) pathway drives cancer progression through direct regulation of most oncogenic properties. Here, we report that PI3K pathway signaling up-regulates cancer cell proliferation, metastasis and angiogenesis through modulation of cancer metabolism. These oncogenic metabolic processes were disrupted, by a novel PI3K inhibitor, 3-Dihydro-2-(naphthalene-1-yl) quinazolin-4(1H)-one (DHNQ) in colon cancer cells. DHNQ inhibited the Warburg effect and lipid synthesis by reducing gene expression of glycolytic and lipogenesis regulatory enzymes. This downregulation at gene level by DHNQ inhibited metabolic flux to repress proliferation, migration and invasion characteristics of colon cancer. Furthermore, the metabolic attenuation caused repression of in vitro/in vivo angiogenesis providing new insights in PI3K regulated angiogenesis via metabolic alterations. Our results suggest that multifaceted targeting of oncogenic metabolism by their upstream PI3K regulatory signaling may be an effective cancer treatment approach.

A novel quinazolinone derivative induces cytochrome c interdependent apoptosis and autophagy in human leukemia MOLT-4 cells

Graphical abstract

A novel PI3K axis selective molecule exhibits potent tumor inhibition in colorectal carcinogenesis

Phosphatidylinositol‐3‐kinase (PI3K) pathway deregulation is responsible for initiation, chemo‐resistance, and poor prognosis of colorectal cancer (CRC). Therefore, PI3K pathway inhibition can provide a plausible way of attaining CRC treatment. We report PI3K target specific synthesis and selection of a potent molecule, that is, 2,3‐dihydro‐2‐(naphthalene‐1‐yl) quinazolin‐4(1H)‐one (DHNQ) from quinazolinone series based on the structural activity relationship after evaluation in diverse cancers. This molecule inhibited the PI3K enzyme activity and transcriptional as well as translational expression levels in colorectal cancer (CRC) models. This was associated with subsequent decrease in phosphorylation of its downstream effector proteins, that is, p‐Akt(Ser‐473) and p‐mTORC1(Ser‐2448) and decreased ERK signaling. Furthermore, DHNQ decreased expression of cyclins that caused G1 arrest and decreased Bcl‐2/Bax ratio after mitochondrial membrane potential loss, reactive oxygen species generation, and an increase in cytosolic Ca2+ loads that is responsible for the decreased CRC cell proliferation and survival. These biochemical changes triggered apoptotic cell death with altered autophagic Beclin‐1 and LC3β expression. It seemed that the PI3K‐Akt signaling regulated apoptosis and autophagy through different mechanisms but mTORC1 mediated autophagy appeared not to be involved in the cell death induction by DHNQ. The molecule also showed significant anticancer efficacy in in vivo tumor models without any mortality indicating its non‐toxic nature with possible clinical significance. Overall, the selective elucidation of DHNQ molecular mechanism will provide the possible strategies for the clinical development in CRC that may respond to this specific, potent and novel P13K inhibitor.