Chinmay Chowdhury

Studies on copper(I) catalysed cross-coupling reactions : A convenient and facile method for the synthesis of diversely substituted α,β-acetylenic ketones☆

Abstract Terminal alkynes reacted with acid chlorides in the presence of cuprous iodide as a catalyst in Et 3 N at room temperature yielding a number of α,β-acetylenic ketones in good to excellent yields.

Total synthesis of seco-lateriflorone

A convergent strategy toward the synthesis of lateriflorone ( 5 ) is described. Our approach is based on biosynthetic considerations and draws on a sequence of prenylation, oxygenation and Claisen reactions for the construction of chromenequinone 6 , and a tandem Claisen/Diels–Alder reaction cascade for the synthesis of caged tricycle 7 . Union of fragments 6 and 7 led to the synthesis of seco -lateriflorone ( 49 ).

Synthesis, cytotoxicity, and structure―activity relationship (SAR) studies of andrographolide analogues as anti-cancer agent

A series of analogues of andrographolide, prepared through chemo-selective functionalization at C14 hydroxy, have been evaluated for in vitro cytotoxicities against human leukemic cell lines. Two of the analogues (6a, 9b) exhibited significant potency. Preliminary studies on structure-activity relationship (SAR) revealed that the α-alkylidene-γ-butyrolactone moiety of andrographolide played a major role in the activity profile. The structures of the analogues were established through spectroscopic and analytical data.

Expedient and rapid synthesis of 1,2,3-triazolo[5,1-c]morpholines through palladium-copper catalysis.

A one-pot approach using palladium-copper as catalyst has been developed for the synthesis of morpholines fused with 1,2,3-triazole. Good regioselectivity, mild reaction conditions, high yields and short reaction time are the hallmarks of this method.

Copper(I)-catalysed acylation of terminal alkynes

Abstract A facile synthesis of conjugated acetylenic ketones is reported, involving Copper(I) catalysed acylation of terminal alkynes with acyl halides.

Palladium-Catalyzed Approach for the General Synthesis of (E)-2- Arylmethylidene-N-tosylindolines and (E)-2-Arylmethylidene-N-tosyl/nosyltetrahydroquinolines: Access to 2-Substituted Indoles and Quinolines

A facile and efficient method for the synthesis of (E)-2-arylmethylidene-N-tosylindolines and (E)-2-arylmethylidene-N-tosyl/nosyltetrahydroquinoline variants has been developed through palladium-catalyzed cyclocondensation of aryl iodides with readily available 1-(2-tosylaminophenyl)prop-2-yn-1-ols and their higher homologues, respectively. The proposed reaction mechanism invokes the operation of trans-aminopalladation during cyclization (5/6-exo-dig), which ensures exclusive (E)-stereochemistry in the products. The method is fast, operationally simple, totally regio- and stereoselective, and versatile enough to access a variety of 2-substituted indoles and quinolines. The reactions proceeded efficiently with a wide variety of substrates and afforded the corresponding products in moderate to excellent yields.

Andrographolide Analogue Induces Apoptosis and Autophagy Mediated Cell Death in U937 Cells by Inhibition of PI3K/Akt/mTOR Pathway.

Background Current chemotherapeutic agents based on apoptosis induction are lacking in desired efficacy. Therefore, there is continuous effort to bring about new dimension in control and gradual eradication of cancer by means of ever evolving therapeutic strategies. Various forms of PCD are being increasingly implicated in anti-cancer therapy and the complex interplay among them is vital for the ultimate fate of proliferating cells. We elaborated and illustrated the underlying mechanism of the most potent Andrographolide analogue (AG–4) mediated action that involved the induction of dual modes of cell death—apoptosis and autophagy in human leukemic U937 cells. Principal Findings AG–4 induced cytotoxicity was associated with redox imbalance and apoptosis which involved mitochondrial depolarisation, altered apoptotic protein expressions, activation of the caspase cascade leading to cell cycle arrest. Incubation with caspase inhibitor Z-VAD-fmk or Bax siRNA decreased cytotoxic efficacy of AG–4 emphasising critical roles of caspase and Bax. In addition, AG–4 induced autophagy as evident from LC3-II accumulation, increased Atg protein expressions and autophagosome formation. Pre-treatment with 3-MA or Atg 5 siRNA suppressed the cytotoxic effect of AG–4 implying the pro-death role of autophagy. Furthermore, incubation with Z-VAD-fmk or Bax siRNA subdued AG–4 induced autophagy and pre-treatment with 3-MA or Atg 5 siRNA curbed AG–4 induced apoptosis—implying that apoptosis and autophagy acted as partners in the context of AG–4 mediated action. AG–4 also inhibited PI3K/Akt/mTOR pathway. Inhibition of mTOR or Akt augmented AG–4 induced apoptosis and autophagy signifying its crucial role in its mechanism of action. Conclusions Thus, these findings prove the dual ability of AG–4 to induce apoptosis and autophagy which provide a new perspective to it as a potential molecule targeting PCD for future cancer therapeutics.

Apoptotic and Autophagic Effects of Sesbania grandiflora Flowers in Human Leukemic Cells

Background Identification of cytotoxic compounds that induce apoptosis has been the mainstay of anti-cancer therapeutics for several decades. In recent years, focus has shifted to inducing multiple modes of cell death coupled with reduced systemic toxicity. The plant Sesbania grandiflora is widely used in Indian traditional medicine for the treatment of a broad spectrum of diseases. This encouraged us to investigate into the anti-proliferative effect of a fraction (F2) isolated from S. grandiflora flowers in cancer cells and delineate the underlying involvement of apoptotic and autophagic pathways. Principal Findings Using MTT based cell viability assay, we evaluated the cytotoxic potential of fraction F2. It was the most effective on U937 cells (IC50∶18.6 µg/ml). Inhibition of growth involved enhancement of Annexin V positivity. This was associated with elevated reactive oxygen species generation, measured by flow cytometry and reduced oxygen consumption – both effects being abrogated by anti-oxidant NAC. This caused stimulation of pro-apoptotic proteins and concomitant inhibition of anti-apoptotic protein expressions inducing mitochondrial depolarization, as measured by flow cytometry and release of cytochrome c. Interestingly, even with these molecular features of apoptosis, F2 was able to alter Atg protein levels and induce LC3 processing. This was accompanied by formation of autophagic vacuoles as revealed by fluorescence and transmission electron microscopy – confirming the occurrence of autophagy. Eventually, F2 triggered caspase cascade – executioners of programmed cell death and AIF translocation to nuclei. This culminated in cleavage of the DNA repair enzyme, poly (ADP-ribose) polymerase that caused DNA damage as proved by staining with Hoechst 33258 leading to cell death. Conclusions The findings suggest fraction F2 triggers pro-oxidant activity and mediates its cytotoxicity in leukemic cells via apoptosis and autophagy. Thus, it merits consideration and further investigation as a therapeutic option for the treatment of leukemia.

A rapid and facile method for the general synthesis of 3-aryl substituted 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines and their ring fused analogues

We report a general and facile method that provides rapid entry into 3-aryl substituted 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines and their ring fused analogues in one-pot under palladium-copper catalysis. The methodology utilises simple and easily available substrates of broad range. The applicability of this reaction for the synthesis of optically active products has been demonstrated. A plausible reaction mechanism has also been proposed.

An efficient strategy for the general synthesis of 3-aryl substituted pyrazolo[5,1-c][1,4]benzoxazines and pyrazolo[1,5-a][1,4]benzodiazepin-6(4H)-ones

An efficient strategy for the general synthesis of 3-aryl substituted pyrazolo[5,1-c][1,4]benzoxazines and pyrazolo[1,5-a][1,4]benzodiazepin-6(4H)-ones has been developed using intramolecular 1,3-dipolar cycloaddition. The hydrazonoyl chloride, the precursor of the cycloadduct, is accessed easily through a two-step reaction carried out in one-pot. It is then used without purification for the base induced formation of the nitrilimine, which undergoes subsequent in situ intramolecular cycloaddition with an alkyne to afford the desired product. The reaction protocol has also been applied in bis-heteroannulation and in the synthesis of uracil derivatives of biological interest. The operational simplicity of the process, the use of cheap starting materials, and the relatively short reaction times required make the process convenient and practical.