Cirandur Suresh Reddy

Binding and molecular dynamics studies of 7-hydroxycoumarin derivatives with human serum albumin and its pharmacological importance

Human serum albumin (HSA) is one of the most widely studied proteins and is an important plasma protein responsible for binding and transport of many exogenous and endogenous drugs. Coumarin derivatives play a critical role as anticancer, antidiabetic, anticoagulant, and analgesic agents. Here we have studied the cytotoxic activity of 7-hydroxycoumarin derivatives (7HC-1, 7HC-2, and 7HC-3) on mouse macrophage (RAW 264.7) cell lines. These studies revealed that 7-hydroxycoumarin derivatives caused an increased inhibition in growth of inflamed macrophages in a concentration-dependent manner with an IC50 of 78, 63, and 50 μM. Further studies, using fluorescence, circular dichroism spectroscopy, molecular docking, and molecular dynamics methods, show binding of 7HC (umbelliferone) derivatives with HSA at physiological pH 7.2. The binding constant of 7HC derivatives with HSA obtained from fluorescence emission was found to be K7HC-1 = 4.6 ± 0.01 × 10(4) M(-1), K7HC-2 = 1.3 ± 0.01 × 10(4) M(-1), and K7HC-3 = 7.9 ± 0.01 × 10(4) M(-1) which corresponds to -6.34 kcal/mol, -5.58 kcal/mol, and -6.65 kcal/mol of free energy. In contrast, the binding of these coumarin derivatives (7HC-1, 7HC-2, and 7HC-3) was almost negligible with α-1-glycoprotein (AGP). Circular dichroism (CD) studies revealed a decreased α-helix content with an increase in the β-sheets and random coils in HSA upon interaction with coumarin derivatives, suggesting a partial unfolding of the HSA secondary structure. Site probe studies with phenylbutazone (Site I) and ibuprofen (Site II) indicated that 7HC derivatives specifically bind to sub domains IIIA and IIIB of HSA which is further corroborated by molecular dynamics and docking studies suggesting that binding is specific in nature. The values of free energies and binding constants coincide for both experimental and in silico analysis and suggest that there are hydrophobic interactions when coumarin derivatives bind to HSA. Molecular dynamics studies showed that the HSA-coumarin complex reaches an equilibration state at around 3.5 ns which indicates that the HSA-coumarin complexes were stable. Thus these interactions play a central role in development of coumarin derivative-inspired drugs.

Elucidation of the Binding Mechanism of Coumarin Derivatives with Human Serum Albumin

Coumarin is a benzopyrone which is widely used as an anti-coagulant, anti-oxidant, anti-cancer and also to cure arthritis, herpes, asthma and inflammation. Here, we studied the binding of synthesized coumarin derivatives with human serum albumin (HSA) at physiological pH 7.2 by using fluorescence spectroscopy, circular dichroism spectroscopy, molecular docking and molecular dynamics simulation studies. By addition of coumarin derivatives to HSA the maximum fluorescence intensity was reduced due to quenching of intrinsic fluorescence upon binding of coumarin derivatives to HSA. The binding constant and free energy were found to be 1.957±0.01×105 M−1, −7.175 Kcal M−1 for coumarin derivative (CD) enamide; 0.837±0.01×105 M−1, −6.685 Kcal M−1 for coumarin derivative (CD) enoate, and 0.606±0.01×105 M−1, −6.49 Kcal M−1 for coumarin derivative methylprop (CDM) enamide. The CD spectroscopy showed that the protein secondary structure was partially unfolded upon binding of coumarin derivatives. Further, the molecular docking studies showed that coumarin derivatives were binding to HSA at sub-domain IB with the hydrophobic interactions and also with hydrogen bond interactions. Additionally, the molecular dynamics simulations studies contributed in understanding the stability of protein-drug complex system in the aqueous solution and the conformational changes in HSA upon binding of coumarin derivatives. This study will provide insights into designing of the new inspired coumarin derivatives as therapeutic agents against many life threatening diseases.

Design, Synthesis and Anti Colon Cancer Activity Evaluation of Phosphorylated Derivatives of Lamivudine (3TC)

The novel phosphorylated derivatives of Lamivudine (5a-5l) as potential anti colon cancer agents are synthe- sized. These title compounds are designed based on the basic pyrimidine derivative lamivudine as a starting compound and reacted with various phosphorodichloridates followed by the introduction of bioactive groups at the phosphorus. Their structures were characterized by IR, 1 H, 13 C, 31 P NMR and mass spectral analyses. All the compounds were evaluated for their anti colon cancer activity against COLO-205 cell lines in vitro studies. Among them 5a and 5b emerged as lead compounds with 0.003 μM and 0.0001 μM values.

Total synthesis of ( )-seimatopolide A

Total synthesis of 10-membered lactone (+)-seimatopolide A is presented from furfural. Key reactions in the present strategy include the effective use of furan as a E-but-2-ene-1,4-dione surrogate, Nagao acetate aldol reaction, and Shiina lactonization.

Polyethylene glycol in water: a simple and environment friendly medium for C–P bond formation

A simple and highly efficient protocol for C–P bond formation under catalyst free conditions at an ambient temperature is reported by using polyethylene glycol in water as an efficient recyclable medium without using any organic co-solvent or additive.

Supramolecular catalysis by β-cyclodextrin for the synthesis of kojic acid derivatives in water

An efficient and green method has been developed for the synthesis of kojic acid derivatives by employing 20 mol% β-cyclodextrin in aqueous media. The high functional group tolerance and shorter reaction times make this method suitable for the synthesis of kojic acid derivatives with a wide substitution pattern.

Design, Synthesis, Antioxidant, and Anti‐Breast Cancer Activities of Novel Diethyl(alkyl/aryl/heteroarylamino)(4‐(pyridin‐2‐yl)phenyl)methylphosphonates

A series of new diethyl(alkyl/aryl/heteroarylamino)(4‐(pyridine‐2‐yl)phenyl)methylphosphonates (4a–t) were synthesized via three‐component Kabachnik–Fields reaction of 4‐(pyridin‐2‐yl)benzaldehyde, diethylphosphite and various primary amines, catalyzed by cupric acetate monohydrate [Cu(OAc)2 · H2O] under solvent‐free and microwave irradiation conditions. Their computational docking analysis supported them as good therapeutic agents to the breast cancer aromatase enzyme and ascertained 4a, 4h, 4m, 4n, and 4t as potential molecules with good binding affinities varying from −9.0 to −9.6 kcal/mol and containing the 4‐(pyridine‐2‐yl)phenyl moiety as a pharmacophore. Their in vitro screening performed for the anti‐cell proliferation activity against MBC‐MCF7 cells by MTT and Trypan blue assays confirmed 4m, 4n, and 4q as promising compounds to sustain a low percentage of cell viability at 20 µg/mL concentration. These compounds were also evaluated for their antioxidant activity by the DPPH method and the results established that compounds 4m, 4n, and 4q show around 10% higher activity than the standard antioxidant ascorbic acid.

Synthesis and bio-evaluation of novel 7-hydroxy coumarin derivatives via Knoevenagel reaction

Coumarin and 7-hydroxy coumarins have great significance as natural fragrances, having a characteristic odour like vanilla beans and their hydroxy position at 7 has importance in biosynthesis. Treatment of 8-formyl-7-hydroxy coumarin with N,N-disubstituted cyano acetamides in the presence of piperidine afforded novel 8-substituted-7-hydroxy coumarin derivatives. Their structures were characterized by IR, 1H, 13C NMR, mass spectral and elemental analysis data. Two out of these 12 compounds, i.e. 2-Cyano-3-(7-hydroxy-2-oxo-2H-chromen-8-yl)-N-[2-(2-methoxy-phenoxy)-ethyl]-acrylamide and 2-Cyano-N-(2,5-dihydro-thiazol-2-yl)-3-(7-hydroxy-2-oxo-2H-chromen-8-yl)-acryl amide showed enhanced in vitro antifungal activity against Candida albicans and Aspergillus niger vis-à-vis standard, i.e. fluconazole, and enhanced in vitro antibacterial activity against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa vis-à-vis standard, i.e. norfloxacin.Graphical Abstract.

Ytterbium perfluorooctanoate [Yb(PFO)3]: a novel and efficient catalyst for the synthesis of tetrahydrobenzo[a]xanthene-11-ones under microwave irradiation

Ytterbium perfluorooctanoate [Yb(PFO)3] was found to be an efficient catalyst for the microwave assisted synthesis of tetrahydrobenzo[a]xanthene-11-ones by the one-pot condensation of 2-naphthol, aldehydes and 1,3-dicarbonyl compound under solvent-free conditions. The major advantages of this novel method are short reaction time, high yields, reusability of the catalyst and the absence of any volatile and hazardous organic solvents.

Investigation of binding mechanism of novel 8-substituted coumarin derivatives with human serum albumin and α-1-glycoprotein

Coumarin molecules have biological activities possessing lipid-controlling activity, anti-hepatitis C activity, anti-diabetic, anti-Parkinson activity, and anti-cancer activity. Here, we have presented an inclusive study on the interaction of 8-substituted-7-hydroxy coumarin derivatives (Umb-1/Umb-2) with α-1-glycoprotein (AGP) and human serum albumin (HSA) which are the major carrier proteins in the human blood plasma. Binding constants obtained from fluorescence emission data were found to be KUmb-1=3.1 ± .01 × 104 M−1, KUmb-2 = 7 ± .01 × 104 M−1, which corresponds to −6.1 and −6.5 kcal/mol of free energy for Umb-1 and Umb-2, respectively, suggesting that these derivatives bind strongly to HSA. Also these molecules bind to AGP with binding constants of KUmb-1-AGP=3.1 ± .01 × 103 M−1 and KUmb-2-AGP = 4.6 ± .01 × 103 M−1. Further, the distance, r between the donor (HSA) and acceptor (Umb-1/Umb-2) was calculated based on the Forster’s theory of non-radiation energy transfer and the values were observed to be 1.14 and 1.29 nm in Umb-1–HSA and Umb-2–HSA system, respectively. The protein secondary structure of HSA was partially unfolded upon binding of Umb-1 and Umb-2. Furthermore, site displacement experiments with lidocaine, phenylbutazone (IIA), and ibuprofen (IIIA) proves that Umb derivatives significantly bind to subdomain IIIA of HSA which is further supported by docking studies. Furthermore, Umb-1 binds to LYS402 with one hydrogen bond distance of 2.8 Å and Umb-2 binds to GLU354 with one hydrogen bond at a distance of 2.0 Å. Moreover, these molecules are stabilized by hydrophobic interactions and hydrogen bond between the hydroxyl groups of carbon-3 of coumarin derivatives.