Synthesis of mixed musks via Eschenmoser-Tanabe fragmentation, enyne metathesis and Diels-Alder reaction as key steps.

Musk analogues containing different macrocyclic ring systems as well as different annulated ring systems were synthesised by a simple and useful strategy. This strategy includes Eschenmoser-Tanabe fragmentation, enyne metathesis and Diels-Alder reaction as key steps. Starting from easily available (n) macrocyclic ketones, (n + 3) macrocyclic systems were assembled using the basic organic reactions.

Regioselective Ring Expansion of 3-Ylideneoxindoles with Tosyldiazomethane (TsDAM): A Metal-Free and Greener Approach for the Synthesis of Pyrazolo-[1,5-c]quinazolines.

An efficient, metal-free approach to access pyrazolo-[1,5-c]quinazolines with 3-ylideneoxindoles and tosyldiazomethane (TsDAM) under mild aqueous reaction conditions has been developed and the solvent involvement in the present reaction has also been explored for the first time. This greener approach involves 1,3-dipolar cycloaddition, regioselective ring expansion, followed by the elimination of tosyl group with aqueous base in a single operation, and the product can be isolated in high purity without column chromatographic separation. The method is also compatible with a large variety of functional groups, providing good to excellent yields in water, thus resulting in a decrease of environmental impact in the pharmaceutical industry.

Synthesis of Substituted Cinnamido Linked Quinazolinone Congeners as Potential Anticancer Agents via Mitochondrial Dependent Intrinsic Apoptotic Pathway.

BACKGROUND: The synthesis of novel heterocyclic scaffolds with amide functionality is a key research area due to their plethora of medicinal applications. The present study aims to explore the synthesis of new cinnamido linked quinazolinone congeners and their potential as anticancer agents. METHODS: Cytotoxicity evaluation, Cell cycle analysis, JC-1 staining, ROS, Annexin V assays, AO/EB, DAPI nuclear staining, Colony-forming assay and Western blot analysis. RESULTS: Among the synthesized compounds, 5eb and 5fc have shown promising cytotoxic activity with an IC50 value of 3.89±1.01µM and 4.05±0.62µM against HeLa cell lines. The flow-cytometry analysis demonstrated that the compound 5eb arrested the sub-G1 phase of the cell cycle and induced apoptosis. Furthermore, the compound 5eb triggered the collapse of mitochondrial membrane potential (ΔΨm), which was assessed by JC-1 staining and also induced the generation of Reactive Oxygen Species. An increase in the expression of proapoptotic proteins such as Bax, p53, cleaved PARP and cleaved caspase-3 by 5eb confirmed the activation of the mitochondrial-dependent intrinsic apoptosis pathway. CONCLUSION: Our results suggest that compound 5eb and 5fc of cinnamido linked quinazolinone derivatives could serve as potential leads in the development of novel chemotherapeutic agents.

A metal-free approach for the synthesis of amides/esters with pyridinium salts of phenacyl bromides via oxidative C-C bond cleavage.

An efficient, simple, and metal-free synthetic approach for the N- and O-benzoylation of various amines/benzyl alcohols with pyridinium salts of phenacyl bromides is demonstrated to generate the corresponding amides and esters. This protocol facilitates the oxidative cleavage of a C-C bond followed by formation of a new C-N/C-O bond in the presence of K2CO3. Various pyridinium salts of phenacyl bromides can be readily transformed into a variety of amides and esters which is an alternative method for the conventional amidation and esterification in organic synthesis. High functional group tolerance, broad substrate scope and operational simplicity are the prominent advantages of the current protocol.

Synthesis of DNA interactive C3-trans-cinnamide linked ß-carboline conjugates as potential cytotoxic and DNA topoisomerase I inhibitors.

A series of new C3-trans-cinnamide linked ß-carboline conjugates has been synthesized by coupling between various ß-carboline amines and substituted cinnamic acids. Evaluation of their anti-proliferative activity against a panel of selected human cancer cell lines such as A549 (lung cancer), MCF-7 (breast cancer), B16 (melanoma), HeLa (cervical cancer) and a normal cell line NIH3T3 (mouse embryonic fibroblast cell line), suggested that the newly designed conjugates are considerably active against all the tested cancer cell lines with IC50 values 13-45 nM. Moreover, the conjugates 8v and 8x were the most active against MCF-7 cells (14.05 nM and 13.84 nM respectively) and also even potent on other cell lines tested. Further, detailed investigations such as cell cycle analysis, apoptosis induction study, topoisomerase I inhibition assay, DNA binding affinity and docking studies revealed that these new conjugates are DNA interactive topoisomerase I inhibitors.

Regioselective Ring Expansion of Isatins with In Situ Generated α-Aryldiazomethanes: Direct Access to Viridicatin Alkaloids.

A novel efficient one-pot regioselective ring-expansion reaction of isatins with in situ generated α-aryl/heteroaryldiazomethanes for the construction of viridicatin alkaloids has been described under metal-free conditions. The utility of this protocol is further demonstrated in the synthesis of naturally occurring viridicatin, viridicatol, and substituted 3- O-methyl viridicatin and their scale up.

Synthesis of podophyllotoxin linked ß-carboline congeners as potential anticancer agents and DNA topoisomerase II inhibitors.

A series of new podophyllotoxin linked ß-carboline congeners have been synthesized by coupling various substituted ß-carboline acids with 4ß-aminopodophyllotoxin. Evaluation of their anticancer activity against a panel of human cancer cell lines such as lung cancer (A549), prostate cancer (DU-145), MDA MB-231 (breast cancer), HT-29 (colon cancer) and HeLa (cervical cancer) suggested that 7i and 7j are the most cytotoxic compounds with IC50 values of 1.07 ±â€¯0.07 µM and 1.14 ±â€¯0.16 respectively against DU-145 cell line. Further, detailed biological studies such as cell cycle analysis, topoisomerase II inhibition, Comet assay, DNA binding studies and docking studies have revealed that these congeners are DNA interacting topoisomerase II inhibitors.

An efficient one-pot approach for the regio- and diastereoselective synthesis of trans-dihydrofuran derivatives: cytotoxicity and DNA-binding studies.

An operationally facile and high yielding one-pot, three-component protocol has been developed for the preparation of selectively trans-2,3-dihydrofuro[3,2-c]coumarins and trans-1,2-dihydrobenzo[h]furo[3,2-c]quinolinones. This protocol proceeds through a domino Knoevenagel condensation, a Michael addition followed by intramolecular SN2 cyclisation. All the synthesized compounds have been evaluated for their in vitro cytotoxic activity against selected human cancer cell lines. Interestingly, most of the compounds have exhibited considerable cytotoxicity with IC50 values <10 µM in all the tested cell lines. Moreover, these compounds showed higher activity against MCF-7 (breast cancer) cell lines compared to other tested cell lines. Compounds 1g and 1r displayed significant cytotoxicity against all four tested cell lines. Cytotoxicity studies indicated that the toxicity of the synthesized compounds was considerably higher in tumor cells compared to normal cells. The structure-activity relationship studies revealed that the activating groups in these compounds preferably improved the activity compared to the deactivating groups. For a better understanding of the mechanism of action of these compounds, we performed the binding studies with calf thymus DNA (CT-DNA). Both molecular docking studies as well as biophysical studies indicate that these compounds may possess DNA binding affinity through intercalation. Through photocleavage studies, it is evident that they have the potential to cleave pBR322 plasmid DNA strands in a concentration and time dependent manner. In addition, compounds 1g and 1r showed significant topoisomerase II inhibitory activities. Moreover, an in silico study of these synthesized compounds revealed that they possess drug-like properties.

A facile I2-catalyzed synthesis of imidazo[1,2-a]pyridines via sp3 C-H functionalization of azaarenes and evaluation of anticancer activity.

A facile and efficient metal-free, one-pot, three component synthetic protocol has been developed for the synthesis of medicinally important substituted imidazo[1,2-a]pyridines via the iodine-catalysed oxidative amination of benzylic C-H bonds of azaarenes with 2-aminoazines and condensation with isocyanides. The presented methodology offers the advantages of wide substrate scope, moderate reaction conditions, environment friendliness, clean and simple protocol with high atom economy apart from higher yields. The synthesized compounds were screened for their anti-cancer activity in selected human cancer cell lines. Compounds 4a, 4b, 4c, 4i, 7a, 7b and 7m have significant IC50 values ranging from 4.88 ± 0.28 to 14.55 ± 0.74 µM.

Neo-tanshinlactone D-ring modified novel analogues induce apoptosis in human breast cancer cell via DNA damage.

Neo-tanshinlactone (NTL) a natural product is known for its specificity and selectivity towards the breast cancer cells. By NTL D-ring modification approach, 13 new analogues were synthesized (1A-1M). Among them 1J showed the best anticancer activity in MCF-7 (ER+, PR+/-, HER2-), SKBR3 (ER-, PR-, HER2+) and MDA-MB-231 (ER-, PR-, HER2-) cells lines with IC50 value 11.98nM, 23.71nM, and 62.91nM respectively. 1J showed minor grove binding interaction with DNA at AT-rich region and induced DNA double strand breaks (DDSBs). This had triggered several key molecular events involving, activation of ATM, Chk2 and p53, reduction in mitochondrial potential (Δψm) leading to caspase-3 and PARP cleavage mediated apoptosis. These results along with other biochemical studies strongly suggest that novel NTL analogue 1J caused DNA cleavage mediated apoptosis in the breast cancer cells and this may serve as potential lead for future breast cancer treatment.

Design and synthesis of dithiocarbamate linked ß-carboline derivatives: DNA topoisomerase II inhibition with DNA binding and apoptosis inducing ability.

A series of new ß-carboline-dithiocarbamate derivatives bearing phenyl, dithiocarbamate and H/methyl substitutions at position-1, 3 and 9, respectively, were designed and synthesized. These derivatives 8a-l and 13a-l and their starting precursors (7 a-d and 12 a-d) have been evaluated for their in vitro cytotoxic activity on selected human cancer cell lines. Among the derivatives tested, 7 c, 12 c, 8 a, 8 d, 8 i, 8 j, 8 k, 8l and 13 d-l exhibited considerable cytotoxicity against most of the tested cancer cell lines (IC50<10µM). Interestingly, most of the derivatives (8 a-l and 13a-l) exhibited enhanced activity than their precursors (7 a-d and 12 a-d), which indicates that the combination of dithiocarbamate with ß-carboline enhances the cytotoxicity of 8 a-l and 13 a-l. Moreover, the derivatives 8 j and 13 g exhibited significant cytotoxic activity with IC50 values of 1.34 µM and 0.79 µM on DU-145 cancer cells, respectively. Further, the induction of apoptosis by these derivatives was confirmed by Annexin V-FITC and Hoechst staining assays. However, both biophysical as well as molecular docking studies suggested a combilexin-type of interaction between these derivatives and DNA, unlike simple ß-carbolines. With a view to understand their mechanism of action, DNA topoisomerase II (topo II) inhibition assay was also performed. Overall, the present study emphasizes the importance of linking a dithiocarbamate moiety to the ß-carboline scaffold for exhibiting profound activity.

PhI(OAc)2-mediated one-pot oxidative decarboxylation and aromatization of tetrahydro-ß-carbolines: synthesis of norharmane, harmane, eudistomin U and eudistomin I.

Iodobenzene diacetate was employed as a mild and efficient reagent for one-pot oxidative decarboxylation of tetrahydro-ß-carboline acids and dehydrogenation of tetrahydro-ß-carbolines to access the corresponding aromatic ß-carbolines. To the best of our knowledge this is the first synthesis of ß-carbolines via a one-pot oxidative decarboxylation at ambient temperature. The utility of this protocol has been demonstrated in the synthesis of ß-carboline alkaloids norharmane (2o), harmane (2p), eudistomin U (9) and eudistomin I (12).

Asymmetric Michael addition of ketones to nitroolefins: pyrrolidinyl-oxazole-carboxamides as new efficient organocatalysts.

Chiral pyrrolidinyl-oxazole-carboxamides were synthesized and used as efficient new organocatalysts for the asymmetric Michael addition of ketones with nitroalkenes under solvent-free conditions. Gratifyingly, the corresponding Michael adducts were obtained in higher yields (up to 99%) and excellent stereoselectivities (up to >99/1 dr and 99% ee). Transition state models have been proposed to account for the high enantio- and diastereoselectivity of these Michael addition reactions and also the energetics have been investigated using density functional methods. These results support the preferential formation of syn-products by the approach of trans-ß-nitrostyrene through the re-face of anti-enamine.