Mahanimbine isolated from Murraya koenigii inhibits P-glycoprotein involved in lung cancer chemoresistance.

P-glycoprotein (P-gp), a transmembrane glycoprotein, is mainly involved in lung cancer multidrug resistance. Several P-gp inhibitors have been developed to enhance the efficacy of chemotherapeutics and overcome drug resistance. However, most of them failed in the clinical stages due to undesirable side effects. Therefore, there is a requirement to develop P-gp inhibitors from natural sources. Dietary spice bioactives have been well-known for their anticancer activities. However, their role in modulating the P-gp activity has not been well investigated. Therefore, we have screened for the potential bioactives from various spice plants with P-gp modulatory activity using computational molecular docking analysis. The computational analysis revealed several key bioactives from curry leaves, specifically mahanimbine, exhibited a strong binding affinity with P-gp. Unfortunately, mahanimbine is available with few commercial sources at very high prices. Therefore, we prepared a curry leaves extract and isolated mahanimbine by a novel, yet simple, extraction method that requires less time and causes minimum environmental hazards. After purification, structure, and mass were confirmed for the isolated compound by IR spectrum and LC-MS/MS analysis, respectively. In the mechanistic study, hydrolysis of ATP and substrate efflux by P-gp are coupled. Hence, ATP binding at the ATPase-binding site is one of the fundamental steps for the P-gp efflux cycle. We found that mahanimbine demonstrated to stimulate P-gp ATPase activity. Concurrently, it enhanced the intracellular accumulation of P-gp substrates Rhodamine 123 and Hoechst stain, which indicates that mahanimbine modulates the function of P-gp. In addition, we have analyzed the complementary effect of mahanimbine with the chemotherapeutic drug gefitinib. We found that mahanimbine synergistically enhanced gefitinib efficiency by increasing its intracellular accumulation in lung cancer cells. Overall, mahanimbine has been shown to be a potent P-gp modulator. Therefore, mahanimbine can be further developed as a potential candidate to overcome chemoresistance in lung cancer.

Thermal Energy Electrons and OH-Radicals Induce Strand Breaks in DNA in an Aqueous Environment: Some Salts Offer Protection Against Strand Breaks.

Electrons and •OH-radicals have been generated by using low-energy laser pulses of 6 ns duration (1064 nm wavelength) to create plasma in a suspension of plasmid DNA (pUC19) in water. Upon thermalization, these particles induce single and double strand breakages in DNA along with possible base oxidation/base degradation. The time-evolution of the ensuing structural modifications has been measured; damage to DNA is seen to occur within 30 s of laser irradiation. The time-evolution is also measured upon addition of physiologically relevant concentrations of salts containing monovalent, divalent, or trivalent alkali ions. It is shown that some alkali ions can significantly inhibit strand breakages while some do not. The inhibition is due to electrostatic shielding of DNA, but significantly, the extent of such shielding is seen to depend on how each alkali ion binds to DNA. Results of experiments on strand breakages induced by thermalized particles produced upon plasma-induced photolysis of water, and their inhibition, suggest implications beyond studies of DNA; they open new vistas for utilizing simple nanosecond lasers to explore the effect of ultralow energy radiation on living matter under physiologically relevant conditions.

Strong Strand Breaks in DNA Induced by Thermal Energy Particles and Their Electrostatic Inhibition by Na+ Nanostructures.

Low-power laser pulses of 6 ns duration (1064 nm wavelength) have been used to create plasma in an aqueous solution of plasmid DNA (pUC19). Thermal energy electrons and •OH radicals in the plasma induce strand breakages in DNA, including double strand breaks and possible base oxidation/base degradation. The time evolution of these modifications shows that it takes barely 30 s for damage to DNA to occur. Addition of physiologically relevant concentrations of a salt (NaCl) significantly inhibits such damage. We rationalize such inhibition using simple electrostatic considerations. The observation that DNA damage is induced by plasma-induced photolysis of water suggests implications beyond studies of DNA and opens new vistas for using simple nanosecond lasers to probe how ultralow energy radiation may affect living matter under physiological conditions.

Effect of nucleants in photothermally assisted crystallization.

Laser-induced crystallization is emerging as a promising technique to crystallize biomolecules like amino acids and proteins. The use of external materials as nucleants and novel seeding methods open new paths for protein crystallization. We report here the results of experiments that explore the effect of nucleants on laser-based crystallization of microlitre droplets of small molecules, amino acids, and proteins. The role of parameters like solute concentration, droplet volume, type and size of the nucleant, and laser power, are systematically investigated. In addition to crystallization of standard molecules like NaCl, KCl, and glycine, we demonstrate the crystallization of negatively (l-histidine), and positively (l-aspartic acid) charged amino acids and lysozyme protein. Single crystal X-ray diffraction and Raman spectroscopy studies unequivocally indicate that the nucleants do not alter the molecular structure of glycine, hydrogen bonding patterns, and packing. Localized vaporization of the solvent near the nucleant due to photothermal heating has enabled us to achieve rapid crystallization - within 3 s - at laser intensities of 0.1 MW cm-2, significantly lower than those reported earlier, with both saturated and unsaturated solutions. The outcome of the current experiments may be of utility in tackling various crystallization problems during the formation of crystals large enough to perform X-ray crystallography.

Synthesis, anticancer, structural, and computational docking studies of 3-benzylchroman-4-one derivatives.

A series of 3-Benzylchroman-4-ones were synthesized and screened for anticancer activity by MTT assay. The compounds were evaluated against two cancerous cell lines BT549 (human breast carcinoma), HeLa (human cervical carcinoma), and one noncancerous cell line vero (normal kidney epithelial cells). 3b was found to be the most active molecule against BT549 cells (IC50 = 20.1 µM) and 3h against HeLa cells (IC50 = 20.45 µM). 3b also exhibited moderate activity against HeLa cells (IC50 = 42.8 µM). The molecular structures of 3h and 3i were solved by single crystal X-ray crystallographic technique. Additionally, the molecular docking studies between the tumour suppressor protein p53 with the lead compound 3h, which exhibited better anticancer activity against HeLa cells was examined.

Bisindole-oxadiazole hybrids, T3P® -mediated synthesis, and appraisal of their apoptotic, antimetastatic, and computational Bcl-2 binding potential.

In the pursuit of novel anticancer leads, new bisindole-oxadiazoles were synthesized using propyl phosphonic anhydride as a mild and efficient reagent. The molecule, 3-[5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-1H-indole (3a) exhibited selective cytotoxicity to MCF-7 cells with a cell cycle arrest in the G1 phase. The mechanism of cytotoxicity of 3a involved caspase-2-dependent apoptotic pathway with characteristic apoptotic morphological alterations as observed in acridine orange/ethidium bromide and Hoechst staining. The wound healing migratory assay exhibited an intense impairment in the motility of MCF-7 cells on incubation with 3a. Docking simulations with anti-apoptotic protein Bcl-2, which is also involved in cancer metastasis displayed good affinity and high binding energy of 3a into the well characterized BH3 binding site. The positive correlation between the Bcl-2 binding studies and the results of in vitro investigations exemplifies compound 3a as a lead molecule exhibiting MCF-7 differential cytotoxicity via apoptotic mode of cell death in addition to its anti-metastatic activity.

Data mining of arsenic-based small molecules geometrics present in Cambridge structural database.

Arsenic, ubiquitous in various industrial processes and consumer products, presents both essential functions and considerable toxicity risks, driving extensive research into safer applications. Our investigation, drawing from 7182 arsenic-containing molecules in the Cambridge Structural Database (CSD), outlines their diverse bonding patterns. Notably, 51% of these molecules exhibit cyclic connections, while 49% display acyclic ones. Arsenic forms eight distinct bonding types with other elements, with significant interactions observed, particularly with phenyl rings, O3 and F6 moieties. Top interactions involve carbon, nitrogen, oxygen, fluorine, sulfur, and arsenic itself. We meticulously evaluated average bond lengths under three conditions: without an R-factor cut-off, with R-factor ≤0.075, and with R-factor ≤0.05, supporting the credibility of our results. Comparative analysis with existing literature data enriches our understanding of arsenic's bonding behaviour. Our findings illuminate the structural attributes, molecular coordination, geometry, and bond lengths of arsenic with 68 diverse atoms, enriching our comprehension of arsenic chemistry. These revelations not only offer a pathway for crafting innovative and safer arsenic-based compounds but also foster the evolution of arsenic detoxification mechanisms, tackling pivotal health and environmental challenges linked to arsenic exposure across different contexts.

Elucidating arsenic-bound proteins in the protein data bank: data mining and amino acid cross-validation through Raman spectroscopy.

The International Agency for Research on Cancer has unequivocally classified inorganic arsenic as a Group 1 carcinogen, definitively establishing its potential to induce cancer in humans. Paradoxically, despite its well-documented toxicity, arsenic finds utility as a chemotherapeutic agent. Notable examples include melarsoprol and arsenic trioxide, both employed in the treatment of acute promyelocytic leukemia. In both therapeutic and hazardous contexts, arsenic can accumulate within cellular environments, where it engages in intricate interactions with protein molecules. Gaining a comprehensive understanding of how arsenic compounds interact with proteins holds immense promise for the development of innovative inhibitors and pharmaceutical agents. These advancements could prove invaluable in addressing a spectrum of arsenic-related diseases. In pursuit of this knowledge, we undertook a systematic exploration of the Protein Data Bank, with a focus on 902 proteins intricately associated with 26 arsenic compounds. Our comprehensive investigation reveals insights into the interactions between these arsenical compounds and amino acids located within a 4.0 Å molecular distance from arsenic-binding sites. Our findings identify that cysteine, glutamic acid, aspartic acid, serine, and arginine frequently engage with arsenic. In complement to our computational analyses, we conducted rigorous Raman spectroscopy studies on the top five amino acids displaying robust interactions with arsenic. The results derived from experimental Raman spectroscopy were meticulously compared with our computational assessments, thereby enhancing the reliability and depth of our investigations. The current study presents a multidimensional exploration into the elaborate interplay between arsenic compounds and proteins. By elucidating the specific amino acids that preferentially interact with arsenic, this study not only contributes to the fundamental understanding of these molecular associations but also lays the foundation for future endeavors in drug design and therapeutic interventions targeting arsenic-related illnesses. Our work at the convergence of toxicology, medicine, and molecular biology carries profound implications for advancing our knowledge of arsenic's dual nature as both a poison and a potential cure.

The pathogenic effect of SNPs on structure and function of human TLR4 using a computational approach.

The human toll-like receptor (hTLR) 4 single nucleotide polymorphisms (SNPs) are interconnected with cancer, multiple genetic disorders and other immune-related diseases. The detrimental effect of SNPs in hTLR4 with respect to structure and function has not been explored in depth. The present study concatenates the biological consequences of the SNPs along with structural modifications predicted at the hTLR4 gene. A total of 7910 SNPs of hTLR4 were screened, and 21 damage-causing SNPs were identified. Out of 21, seven are present in the extracellular region, of which three were detected as deleterious and the fourth one as moderate. These three mutations are located in a highly conserved region and influence conformational change. The change leads to the widening of the Leucine-rich repeat (LRR) arc to a maximum of 16.9 Å and a minimum of 8.7 Å. Expansion/shortening of LRR arc, never discussed before, would cause loss of myeloid differentiation factor 2 (MD-2) interactions in the interior and diminish lipopolysaccharide (LPS) responses. Similarly, in all mutant structures, the binding region for HMGB1 and LPS is deflating or in an unsupportive conformation. Thus, SNPs affect the regular signaling cascade and might result in human sepsis, genetic disorders, cancer and other immunological related diseases.Communicated by Ramaswamy H. Sarma.

Traditional medicinal plants against replication, maturation and transmission targets of SARS-CoV-2: computational investigation.

COVID-19 is an infectious pandemic caused by the SARS-CoV-2 virus. The critical components of SARS-CoV-2 are the spike protein (S-protein) and the main protease (Mpro). Mpro is required for the maturation of the various polyproteins involved in replication and transcription. S-protein helps the SARS-CoV-2 to enter the host cells through the angiotensin-converting enzyme 2 (ACE2). Since ACE2 is required for the binding of SARS-CoV-2 on the host cells, ACE2 inhibitors and blockers have got wider attention, in addition to S-protein and Mpro modulators as potential therapeutics for COVID-19. So far, no specific drugs have shown promising therapeutic potential against COVID-19. The current study was undertaken to evaluate the therapeutic potential of traditional medicinal plants against COVID-19. The bioactives from the medicinal plants, along with standard drugs, were screened for their binding against S-protein, Mpro and ACE2 targets using molecular docking followed by molecular dynamics. Based on the higher binding affinity compared with standard drugs, bioactives were selected and further analyzed for their pharmacological properties such as drug-likeness, ADME/T-test, biological activities using in silico tools. The binding energies of several bioactives analyzed with target proteins were relatively comparable and even better than the standard drugs. Based on Lipinski factors and lower binding energies, seven bioactives were further analyzed for their pharmacological and biological characteristics. The selected bioactives were found to have lower toxicity with a higher GI absorption rate and potent anti-inflammatory and anti-viral activities against targets of COVID-19. Therefore, the bioactives from these medicinal plants can be further developed as phytopharmaceuticals for the effective treatment of COVID-19.Communicated by Ramaswamy H. Sarma.

Computational investigations of indanedione and indanone derivatives in drug discovery: Indanone derivatives inhibits cereblon, an E3 ubiquitin ligase component.

BACKGROUND: Cereblon, an extensively studied multifunctional protein, is a Cullin 4-RING E3 ubiquitin ligase complex component. Cereblon is a well-known target of thalidomide and its derivatives. Cereblon is involved in multiple myeloma cell apoptosis. When ligands such as thalidomide and lenalidomide bind to cereblon, it recognizes various neosubstrates based on the ligand shape and properties. We have identified novel CRBN inhibitors, namely DHFO and its analogs, with structural features that are slightly different from thalidomide but stronger cereblon-binding affinity. We selected indanedione and indanone derivatives from the literature to understand and compare their cereblon-mediated substrate recognition potential. METHODS: Computational investigations of possible CRBN inhibitors were investigated by molecular docking with Autodock Vina and DockThor programs. The properties of the compounds' ADME/T and drug-likeness were investigated. A molecular dynamics study was carried out for four selected molecules, and the molecular interactions were analyzed using PCA-based FEL methods. The binding affinity was calculated using the MM/PBSA method. RESULTS: We conducted computational investigations on 68 indanedione and indanone derivatives binding with cereblon. Ten molecules showed better CRBN binding affinity than thalidomide. We studied the drug-likeness properties of the selected ten molecules, and four of the most promising molecules (DHFO, THOH, DIMS, and DTIN) were chosen for molecular dynamics studies. The MM/PBSA calculations showed that the DHFO, already shown to be a 5-LOX/COX2 inhibitor, has the highest binding affinity of - 163.16 kJ/mol with cereblon. CONCLUSION: The selected CRBN inhibitor DHFO has demonstrated the highest binding affinity with cereblon protein compared to other molecules. Thalidomide and its derivatives have a new substitute in the form of DHFO, which produces an interaction hotspot on the surface of the cereblon. Ease of chemical synthesis, low toxicity, versatile therapeutic options, and pleiotropism of DHFO analogs provide an opportunity for exploring clinical alternatives with versatile therapeutic potential for a new category of indanedione molecules as novel modulators of E3 ubiquitin ligases.

Culinary spice bioactives as potential therapeutics against SARS-CoV-2: Computational investigation.

BACKGROUND: Coronavirus disease-2019 (COVID-19) is an infectious pandemic caused by SARS-CoV-2. SARS-CoV-2 main protease (Mpro) and spike protein are crucial for viral replication and transmission. Spike protein recognizes the human ACE2 receptor and transmits SARS-CoV-2 into the human body. Thus, Mpro, spike protein, and ACE2 receptor act as appropriate targets for the development of therapeutics against SARS-CoV-2. Spices are traditionally known to have anti-viral and immune-boosting activities. Therefore, we investigated the possible use of selected spice bioactives against the potential targets of SARS-CoV-2 using computational analysis. METHODS: Molecular docking analysis was performed to analyze the binding efficiency of spice bioactives against SARS-CoV-2 target proteins along with the standard drugs. Drug-likeness properties of selected spice bioactives were investigated using Lipinski's rule of five and the SWISSADME database. Pharmacological properties such as ADME/T, biological functions, and toxicity were analyzed using ADMETlab, PASS-prediction, and ProTox-II servers, respectively. RESULTS: Out of forty-six spice bioactives screened, six bioactives have shown relatively better binding energies than the standard drugs and have a higher binding affinity with at least more than two targets of SARS-CoV-2. The selected bioactives were analyzed for their binding similarities with the standard drug, remdesivir, towards the targets of SARS-CoV-2. Selected spice bioactives have shown potential drug-likeness properties, with higher GI absorption rate, lower toxicity with pleiotropic biological roles. CONCLUSIONS: Spice bioactives have the potential to bind with the specific targets involved in SARS-CoV-2 infection and transmission. Therefore, spice-based nutraceuticals can be developed for the prevention and treatment of COVID-19.

Promising phytochemicals of traditional Himalayan medicinal plants against putative replication and transmission targets of SARS-CoV-2 by computational investigation.

BACKGROUND: Identification and repurposing of therapeutic and preventive strategies against COVID-19 are rapidly undergoing. Several medicinal plants from the Himalayan region have been traditionally used to treat various human disorders. Thus, in our current study, we intended to explore the potential ability of Himalayan medicinal plant (HMP) bioactives against COVID-19 using computational investigations. METHODS: Molecular docking was performed against six crucial targets involved in the replication and transmission of SARS-CoV-2. About forty-two HMP bioactives were analyzed against these targets for their binding energy, molecular interactions, inhibition constant, and biological pathway enrichment analysis. Pharmacological properties and potential biological functions of HMP bioactives were predicted using the ADMETlab and PASS webserver respectively. RESULTS: Our current investigation has demonstrated that the bioactives of HMPs potentially act against COVID-19. Docking results showed that several HMP bioactives had a superior binding affinity with SARS-CoV-2 essential targets like 3CLpro, PLpro, RdRp, helicase, spike protein, and human ACE2. Based on the binding energies, several bioactives were selected and analyzed for pathway enrichment studies. We have found that selected HMP bioactives may have a role in regulating immune and apoptotic pathways. Furthermore, these selected HMP bioactives have shown lower toxicity with pleiotropic biological activities, including anti-viral activities in predicting activity spectra for substances. CONCLUSIONS: Current study results can explore the possibility of HMPs as therapeutic agents against COVID-19.

Conformational analysis of two new organotin(IV) structures completed with a CSD survey.

The conformational flexibilities are studied in two new organotin(IV) complexes, namely, trans-dichloridodimethylbis[N,N',N''-tris(2-chlorobenzyl)phosphoric triamide]tin(IV), [Sn(CH3)2(C21H21Cl3N3OP)2Cl2] or Sn(CH3)2Cl2{OP[NHCH2C6H4(2-Cl)]3}2, (I), and bis(dipropylammonium) tetrachloridodimethylstannate(IV), [(CH3CH2CH2)2NH2]2[Sn(CH3)2Cl4], (II), and their analogous structures from the Cambridge Structural Database (CSD). The conformations are considered based on the N-P=O-Sn torsion angles for (I) and the C-C-C-N, C-C-N-C, C-N-C-C and N-C-C-C torsion angles for the two symmetry-independent [CH3CH2CH2NH2CH2CH2CH3]+ cations in (II), and the ±ac±sp±ac (ac = anticlinal and sp = synperiplanar) and ±ap±ap±ap±ap (ap = antiperiplanar) conformations are observed, respectively. In both structures, the four atoms in the corners of the square-planar segment of the octahedral shape around the Sn atom participate in normal hydrogen-bonding interactions as acceptors, which include two O and two Cl atoms for (I), and four Cl atoms for (II). However, the phosphoric triamide ligands block the environment around the Sn atom and limit the hydrogen-bond pattern to form a supramolecular ribbon assembly, while in the presence of small organic cations in (II), a two-dimensional hydrogen-bonded architecture is achieved. The weak interactions π-π, C-H...π and C-Cl...π in (I), and C-H...Cl in (II) do not change the dimensionality of the hydrogen-bond pattern. The 62 CSD structures analogous to (I), i.e. with an SnOPN3 segment (including 83 entries) fall into four categories of conformations based on the N-P=O-Sn torsion angles. The 132 [(CH3CH2CH2)2NH2]+ cations from 85 CSD structures are classified into seven groups based on the torsion angles noted for (II). Most of the CSD structures adopt the same associated conformations noted for (I) and (II). 15 [Sn(CH3)2Cl4]2- anions extracted from the CSD are compared with the structure of (II).

Effect of OH substitution in 3-benzylchroman-4-ones: crystallographic, CSD, DFT, FTIR, Hirshfeld surface, and energy framework analysis.

3-Benzylchroman-4-ones (homoisoflavanones) are oxygen-containing heterocycles with a sixteen-carbon skeleton. They belong to the class of naturally occurring polyphenolic flavonoids with limited occurrence in nature and possess anti-inflammatory, antibacterial, antihistaminic, antimutagenic, antiviral, and angioprotective properties. Recently, we reported the synthesis and anticancer activity studies of fifteen 3-benzylchroman-4-one molecules, and most of them were proven to be effective against BT549 and HeLa cells. In this work, we report the single-crystal X-ray crystallographic studies of two molecules 3-[(2-hydroxyphenyl)methyl]-3,4-dihydro-2H-1-benzopyran-4-one and 3-[(2,4-dimethoxyphenyl)methyl]-3,4-dihydro-2H-1-benzopyran-4-one. The single crystals were grown using a novel laser-induced crystallization technique. We observed that the 3-benzylchroman-4-one derivative bearing OH substitution at the 2' position adopted different conformation due to formation of dimers through O-H⋯O, and C-H⋯O intermolecular hydrogen bondings. The role of OH substitution in the aforementioned conformational changes was evaluated using density functional theory (DFT), Hirshfeld surface, energy framework and FTIR spectroscopy analysis. In addition, we have carried out a Cambridge Structural Database (CSD) study to understand the conformational changes using five analogue structures. X-ray crystallographic, computational, and spectroscopic studies of 3-benzylchroman-4-ones provided an insight into the role of substitution at benzyl moieties in stabilizing the three-dimensional (3D) structures.

Conformational flexibility in amidophosphoesters: a CSD analysis completed with two new crystal structures of (C6H5O)2P(O)X [X = NHC7H13 and N(CH2C6H5)2].

The crystal structures of diphenyl (cycloheptylamido)phosphate, C19H24NO3P or (C6H5O)2P(O)(NHC7H13), (I), and diphenyl (dibenzylamido)phosphate, C26H24NO3P or (C6H5O)2P(O)[N(CH2C6H5)2], (II), are reported. The NHC7H13 group in (I) provides two significant hydrogen-donor sites in N-H...O and C-H...O hydrogen bonds, needed for a one-dimensional hydrogen-bond pattern along [100] in the crystal, while (II), with a (C6H5CH2)2N moiety, lacks these hydrogen bonds, but its three-dimensional supramolecular structure is mediated by C-H...π interactions. The conformational behaviour of the phenyl rings in (I), (II) and analogous structures from the Cambridge Structural Database (CSD) were studied in terms of flexibility, volume of the other group attached to phosphorus and packing forces. From this study, synclinal (±sc), anticlinal (±ac) and antiperiplanar (±ap) conformations were found to occur. In the structure of (II), there is an intramolecular Cortho-H...O interaction that imposes a +sc conformation for the phenyl ring involved. For the structures from the CSD, the +sc and ±ap conformations appear to be mainly imposed by similar Cortho-H...O intramolecular interactions. The large contribution of the C...H/H...C contacts (32.3%) in the two-dimensional fingerprint plots of (II) is a result of the C-H...π interactions. The differential scanning calorimetry (DSC) analyses exhibit peak temperatures (Tm) at 109 and 81 °C for (I) and (II), respectively, which agree with the strengths of the intermolecular contacts and the melting points.

Effect of biocompatible nucleants in rapid crystallization of natural amino acids using a CW Nd:YAG laser.

Laser-induced crystallization is emerging as an alternative technique to crystallize biomolecules. However, its applications are limited to specific small molecules and some simple proteins, possibly because of the need to use high-intensity, pulsed lasers and relatively long laser irradiation time. Both these factors tend to denature biological molecules. If the laser-intensity and time required to crystallize biomolecules were to be reduced, laser-induced crystallization may well become of widespread utility. We report here the crystallization of nineteen natural amino acids by a laser-induced method in combination with one of three nucleants: aluminum, coconut coir, and peacock feather barbule. We have utilized a low-power, continuous wave (CW) Nd:YAG laser (λ = 1064 nm). The advantages of our method are (i) the use of very small laser powers (60 mW), and (ii) the ability to obtain diffraction quality crystals within a mere few seconds. For most amino acids our method yields several orders of magnitude reduction in crystallization time. The use of biocompatible nucleants like coir fibres and peacock feather barbules are novel; their non-toxic nature may find broad applicability in rapid crystallization of diverse biological molecules.

Efficient T3P® mediated synthesis, differential cytotoxicity and apoptosis induction by indolo-triazolo-thiadiazoles in human breast adenocarcinoma cells.

The limited efficacy of marketed anticancer agents demands the design of novel target-specific hybrid molecules incorporating multiple bioactive pharmacores to combat cancer. In the present study, a one-pot simple and efficient T3P® mediated procedure for the preparation of twelve new 3-(substituted- [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazolo)-1H-indoles with short reaction times, easy workup procedure, good yields, and purity of products is described. Cytotoxicity assay (MTT), flow-cytometric univariate cell cycle analysis, Annexin V-FITC staining and DNA fragmentation for cell death mechanism suggested that compound 3d with chloro-substituted phenyl ring induced enhanced cytotoxicity by an apoptotic pathway with high differential toxicity to breast adenocarcinoma cells (MCF-7) when compared with normal human dermal fibroblast cells. Additionally, the interaction between the BH3 domain of anti-apoptotic proteins Bcl-2 and Bcl-xL with the pharmacophore 3d was examined by molecular docking simulations to assess its potential to induce apoptosis. The docking solutions were proposed to explain the observed selectivity of 3d to Bcl-xL protein. From the present findings, the lead compound, 3d exhibited better anticancer activity when related to the other synthesized molecules with specific action on MCF-7 cells and hence can be considered as a plausible candidate chemo-therapeutic agent, although this warrants further experimentation.

Indole-coumarin-thiadiazole hybrids: An appraisal of their MCF-7 cell growth inhibition, apoptotic, antimetastatic and computational Bcl-2 binding potential.

Cancer therapeutic potential of thiadiazole hybrids incorporating pharmacologically active indole and coumarin moieties have not been explored much. In the current investigation, three new thiadiazole hybrids with spacers of varying lengths linking indole and thiadiazole units were synthesized and their structures were well-established using various spectroscopic techniques. 3-(1-(5-(3-(1H-indol-3-yl)propyl)-1,3,4-thiadiazol-2-ylimino)ethyl)-6-bromo-2H-chromen-2-one (IPTBC) exhibited dose-dependent cytotoxicity in breast adenocarcinoma (MCF-7) cells. The circumvention of apoptosis is a prominent hallmark of cancer and hence triggering apoptosis in specific cancer cells is one of the convenient and widely used approaches for the development of anticancer chemotherapeutics. The induction of apoptosis upon treatment with IPTBC was confirmed by multiple apoptosis assays like Acridine orange-ethidium bromide, Hoechst staining, TUNEL staining, and colorimetric quantification using APOPercentage™ Apoptosis assay. The apoptosis initialisation through the active involvement of caspases was confirmed by caspase profiling tests. The wound healing assay displayed an intense impairment in the motility of MCF-7 cells suggesting the anti-metastatic potential of IPTBC. The ability of IPTBC to inhibit the antiapoptotic Bcl-2 protein by acting as a small molecule BH3 mimetic was explored through docking simulation studies. Although auxiliary investigations are warranted with this promising thiadiazole hybrid IPTBC, the perspective anticancer potential through programmed cell death, anti-metastatic and probable Bcl-2 inhibitory action will enable its further exploration in oncology.