Syed Khalid Yousuf

Importance and synthesis of benzannulated medium-sized and macrocyclic rings (BMRs)

Cyclic molecular frameworks, especially the benzannulated medium-sized and macrocyclic ring (BMR) systems, constitute an integral component of a large number of biologically significant natural or synthetic molecules. Many of these BMR compounds are either approved as drugs or have reached the late developmental stages in clinical trials. Such cyclic systems have been shown to possess great potential, especially in the discovery of new anticancer leads. Efforts from synthetic chemists have led to the development of elegant new strategies for the construction of BMR scaffolds of medicinal importance. This review intends to highlight the importance of benzannulated medium-sized and macrocyclic rings (BMRs) and the strategies developed over the years for their synthesis.

Ring A structural modified derivatives of withaferin A and the evaluation of their cytotoxic potential.

Regio-/stereoselective Michael addition to ring A of withaferin-A was performed using an optimized reaction procedure to synthesise a library of 2,3-dihydro,3-β-substituted withaferin-A derivatives. The analogues thus obtained were evaluated for in vitro cytotoxicity against various human cancer cell lines. 3-Azido analogue exhibited 35-fold increase (IC(50)=0.02-1.9 μM) in cytotoxicity against almost the entire cell lines tested when compared to the parent molecule. However, further modifications of 3-azido analogue with various alkynes under Husigens cycloaddition conditions generated a variety of triazole derivatives with reduced cytotoxicity.

Multicomponent cascade transformation of D-glucal to furan-appended triazole glycoconjugates.

Novel one-pot three- and four-component transformations of D-glucal to furan-based hydroxy triazole glycoconjugates have been achieved by sequential addition of reagents in the presence of Cu(OTf)(2)-Cu powder as catalysts. In general the carbohydrate-derived products were formed with high diastereomeric purity.

PAWR-mediated suppression of BCL2 promotes switching of 3-azido withaferin A (3-AWA)-induced autophagy to apoptosis in prostate cancer cells

An active medicinal component of plant origin with an ability to overcome autophagy by inducing apoptosis should be considered a therapeutically active lead pharmacophore to control malignancies. In this report, we studied the effect of concentration-dependent 3-AWA (3-azido withaferin A) sensitization to androgen-independent prostate cancer (CaP) cells which resulted in a distinct switching of 2 interrelated conserved biological processes, i.e. autophagy and apoptosis. We have observed 3 distinct parameters which are hallmarks of autophagy in our studies. First, a subtoxic concentration of 3-AWA resulted in an autophagic phenotype with an elevation of autophagy markers in prostate cancer cells. This led to a massive accumulation of MAP1LC3B and EGFP-LC3B puncta coupled with gradual degradation of SQSTM1. Second, higher toxic concentrations of 3-AWA stimulated ER stress in CaP cells to turn on apoptosis within 12 h by elevating the expression of the proapoptotic protein PAWR, which in turn suppressed the autophagy-related proteins BCL2 and BECN1. This inhibition of BECN1 in CaP cells, leading to the disruption of the BCL2-BECN1 interaction by overexpressed PAWR has not been reported so far. Third, we provide evidence that pawr-KO MEFs exhibited abundant autophagy signs even at toxic concentrations of 3-AWA underscoring the relevance of PAWR in switching of autophagy to apoptosis. Last but not least, overexpression of EGFP-LC3B and DS-Red-BECN1 revealed a delayed apoptosis turnover at a higher concentration of 3-AWA in CaP cells. In summary, this study provides evidence that 3-AWA is a strong anticancer candidate to abrogate protective autophagy. It also enhanced chemosensitivity by sensitizing prostate cancer cells to apoptosis through induction of PAWR endorsing its therapeutic potential.

Highly Regio- and Stereoselective One-Pot Synthesis of Carbohydrate-Based Butyrolactones

The use of manganese(III) acetate allows the direct synthesis of diverse arrays of [4.3.0] bicyclic carbohydrate-based γ-lactone building blocks from glycals. A mechanism to explain the high regio- and stereoselectivity is proposed. The new reaction has the potential to generate libraries for biological screening.

Medicinal chemistry of dihydropyran-based medium ring macrolides related to aspergillides: selective inhibition of PI3Kα.

A set of nine trans-disubstituted dihydropyran-based medium ring macrolides has been synthesized using d-glucal as chiral pool and evaluated against a panel of three human cancer cell lines and a normal cell line. The synthetic route to the targeted molecule is simple, concise, and high yielding compared to other reported methods. Bioevaluation studies have resulted in the identification of a potent cytotoxic molecule (10) exhibiting dose-dependent growth inhibition against HL-60 cell line with an IC50 value of 1.10 ± 0.075 μM, which is lower than that of naturally occurring molecules of this class and of comparable activity to the synthetic drug fludarubin. Compound 10 inhibits the PI3K/AKT signaling pathway by selectively targeting the p110α subunit of PI3Kα. This leads to mitochondrial stress that causes translocation of cytochrome c from mitochondria to cytosol, which in turn activates caspase-mediated apoptotic cell death. Further in silico docking simulations of four macrolides with p110α subunits have been carried out to visualize the orientation pattern.

Design and synthesis of novel N,N′-glycoside derivatives of 3,3′-diindolylmethanes as potential antiproliferative agents

A library of 34 compounds containing the DIM core have been synthesized and tested for their anticancer efficacy by measuring their cytotoxicity to cancer cell lines A549, HeLa and MCF-7. Some of the selected derivatives were N-glycosylated to increase their efficacy. Compound 7d, an N-glycosylated DIM derivative, was found to be effective at 1.3, 0.3 and 0.9 μmol concentrations against A549, HeLa and MCF-7, respectively. Immunochemistry studies revealed that it could induce apoptosis by upregulating a pro-apoptotic protein Par-4 and concomitantly diminishing the expression of pro-survival proteins Bcl-2 and GRP78. Flow cytometry studies showed that the compound arrested cells in the G1 phase of the cell cycle and significantly abrogated the motility of HeLa cells. Computer docking simulations of 7d with GRP78 suggested its involvement in two H-bonds with Asp78, two H-bonds with Arg290, one with Arg367, and one water mediated H-bond interaction. The interaction patterns also demonstrated that the presence of bromide in the vicinity (within 3.5 A) of Lys294 generates the possibility of a halogen bond, which may also contribute in providing some extra stability to the complex. Hence, compounds of this class will be useful for the design of new anticancer agents.

Domino Transformation of d-Glucal to Racemic α-Substituted α-Hydroxymethyl Furfuryl Derivatives

Lewis acid mediated one-pot transformation of D-glucal in the presence of nucleophiles leads to the formation of racemic alpha-substituted alpha-hydroxymethyl furfuryl derivatives, versatile synthons for biologically active molecules. Transformations using O-, S-, C-, and N-nucleophiles could be achieved readily under mild and scalable conditions. Indium triflate proved to be the catalyst of choice in terms of conversion and regioselectivity.

Cu–Mn bimetallic catalyst for Huisgen [3+2]-cycloaddition

Cu–Mn spinel oxide catalyst has been investigated for the ligand-free Huisgen [3+2] cycloaddition. The copper(I) species required in the cycloaddition reaction has been stabilized in the tetrahedral site of the spinel without the need of a stabilizing agent. The new catalyst is robust and can be reused several times under MW conditions with negligible loss in catalytic activity.

Fe/Al pillared clay catalyzed solvent-free synthesis of bisindolylmethanes using diversely substituted indoles and carbonyl compounds

A fast, solvent-free solid acid mediated synthetic strategy for the synthesis of bisindolylmethanes has been developed. The process is applicable to a wide range of substrates with different protecting group survival properties. Reusability of Fe/Al pillared clay for more than 5 cycles without significant loss of catalytic activity adds to the features of the reaction.