Efficient synthesis of indole-chalcones based glycohybrids and their anticancer activity.

Indole based glycosides belong to the class of pharmacologically active molecules and found in diverse natural compounds. Herein, we report the synthesis of 1,2,3-triazole bridged chirally enriched diverse indole-chalcones based glycohybrids. Three series of glycohybrids were designed and efficiently synthesized using d-glucose, d-galactose and d-mannose derived 1-azido glycosides. The reactions sequence involved were, the synthesis of indole derived chalcones which were formed via Claisen-Schmidt condensation reaction and subsequently N-propargylation which leads to the production of N-propargylated indole-chalcones. The N-propargylated indole-chalcones get transformed into 1,2,3-triazole bridged indole-chalcone based glycohybrids by reacting with 1-azido sugar glycosides under click-chemistry reaction conditions. Further, the biological activity of synthesized glycohybrids (n = 27) was assessed in-vitro against MDA-MB231, MCF-7, MDA-MB453 cancer, and MCF-10A normal cell lines. The selected compounds showed potent anti-oncogenic properties against MCF-7 and MDA-MB231 breast cancer cell line with IC50 values of 1.05 µM and 11.40 µM respectively, with very good selectivity index (SI > 161). The active compounds show better binding affinity as compared to co-crystallized inhibitor 1-(tert-butyl)-3-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP1) with HCK (PTKs) proteins in molecular docking studies.

Applications of Pyrrole and Pyridine-based Heterocycles in Cancer Diagnosis and Treatment.

BACKGROUND: The escalation of cancer worldwide is one of the major causes of economy burden and loss of human resources. According to the American Cancer Society, there will be 1,958,310 new cancer cases and 609,820 projected cancer deaths in 2023 in the United States. It is projected that by 2040, the burden of global cancer is expected to rise to 29.5 million per year, causing a death toll of 16.4 million. The hemostasis regulation by cellular protein synthesis and their targeted degradation is required for normal cell growth. The imbalance in hemostasis causes unbridled growth in cells and results in cancer. The DNA of cells needs to be targeted by chemotherapeutic agents for cancer treatment, but at the same time, their efficacy and toxicity also need to be considered for successful treatment. OBJECTIVE: The objective of this study is to review the published work on pyrrole and pyridine, which have been prominent in the diagnosis and possess anticancer activity, to obtain some novel lead molecules of improved cancer therapeutic. METHODS: A literature search was carried out using different search engines, like Sci-finder, Elsevier, ScienceDirect, RSC etc., for small molecules based on pyrrole and pyridine helpful in diagnosis and inducing apoptosis in cancer cells. The research findings on the application of these compounds from 2018-2023 were reviewed on a variety of cell lines, such as breast cancer, liver cancer, epithelial cancer, etc. Results: In this review, the published small molecules, pyrrole and pyridine and their derivatives, which have roles in the diagnosis and treatment of cancers, were discussed to provide some insight into the structural features responsible for diagnosis and treatment. The analogues with the chromeno-furo-pyridine skeleton showed the highest anticancer activity against breast cancer. The compound 5-amino-N-(1-(pyridin-4- yl)ethylidene)-1H-pyrazole-4-carbohydrazides was highly potent against HEPG2 cancer cell. Redaporfin is used for the treatment of cholangiocarcinoma, biliary tract cancer, cisplatin-resistant head and neck squamous cell carcinoma, and pigmentation melanoma, and it is in clinical trials for phase II. These structural features present a high potential for designing novel anticancer agents for diagnosis and drug development. CONCLUSION: Therefore, the N- and C-substituted pyrrole and pyridine-based novel privileged small Nheterocyclic scaffolds are potential molecules used in the diagnosis and treatment of cancer. This review discusses the reports on the synthesis of such molecules during 2018-2023. The review mainly discusses various diagnostic techniques for cancer, which employ pyrrole and pyridine heterocyclic scaffolds. Furthermore, the anticancer activity of N- and C-substituted pyrrole and pyridine-based scaffolds has been described, which works against different cancer cell lines, such as MCF-7, A549, A2780, HepG2, MDA-MB-231, K562, HT- 29, Caco-2 cells, Hela, Huh-7, WSU-DLCL2, HCT-116, HBL-100, H23, HCC827, SKOV3, etc. This review will help the researchers to obtain a critical insight into the structural aspects of pyrrole and pyridine-based scaffolds useful in cancer diagnosis as well as treatment and design pathways to develop novel drugs in the future.

Repurposing of existing therapeutics to combat drug-resistant malaria.

In the era of drug repurposing, speedy discovery of new therapeutic options for the drug-resistant malaria is the best available tactic to reduce the financial load and time in the drug discovery process. Six anticancer drugs, three immunomodulators and four antibiotics were selected for the repositioning against experimental malaria owing to their mode of action and published literature. The efficacy of existing therapeutics was evaluated against chloroquine-resistant in vitro and in vivo strains of Plasmodium falciparum and P. yoelii, respectively. All the pre-existing FDA-approved drugs along with leptin were primarily screened against chloroquine-resistant (PfK1) and drug-sensitive (Pf3D7) strains of P. falciparum using SYBR green-based antiplasmodial assay. Cytotoxic profiling of these therapeutics was achieved on Vero and HepG2 cell lines, and human erythrocytes. Percent blood parasitemia and host survival was determined in chloroquine-resistant P. yoelii N67-infected Swiss mice using appropriate doses of these drugs/immunomodulators. Antimalarial screening together with cytotoxicity data revealed that anticancer drugs, idelalisib and 5-fluorouracil acquired superiority over their counterparts, regorafenib, and tamoxifen, respectively. ROS-inducer anticancer drugs, epirubicin and bleomycin were found toxic for the host. Immunomodulators (imiquimod, lenalidomide and leptin) were safest but less active in in vitro system, however, in P. yoelii-infected mice, they exhibited modest parasite suppression at their respective doses. Among antibiotics, moxifloxacin exhibited better antimalarial prospective than levofloxacin, roxithromycin and erythromycin. 5-Fluorouracil, imiquimod and moxifloxacin displayed 97.64, 81.18 and 91.77 % parasite inhibition in treated animals and attained superiority in their respective groups thus could be exploited further in combination with suitable antimalarials.

Synthesis and characterization of novel protein nanodots as drug delivery carriers with an enhanced biological efficacy of melatonin in breast cancer cells.

Melatonin is a potent antioxidant, chemotherapeutic and chemo preventive agent against breast cancer. However, its short half-life is one of the major limitations in its application as a therapeutic drug. To overcome this issue, the green-emitting protein nanodot (PND) was synthesized by a one-step hydrothermal method for loading melatonin. The synthesized pH-7 and pH-2 PND showed a quantum yield of 22.1% and 14.0%, respectively. The physicochemical characterization of both PNDs showed similar morphological and functional activities. Furthermore, the biological efficacy of melatonin-loaded PND (MPND) was evaluated in a breast cancer cell line (MDA-MB-231) for live-cell imaging and enhanced nano-drug delivery efficacy. Interestingly, the permeability of neutral pH PND in both cell cytoplasm and nucleus nullifies the limitations of real-time live-cell imaging, and ensures nuclear drug delivery efficacy. Neutral pH PND showed better cell viability and cytotoxicity as a fluorescence bioimaging probe compared to acidic PND. The bioavailability and cell cytotoxicity effect of MPND on MDA-MB-231 breast cancer cells were studied through confocal and migration assay. Results showed that MPND causes enhanced bioavailability, better cellular uptake, and inhibition of the migration of breast cancer cells as compared to the drug alone. Besides, the synthesized MPND showed no sign of fluorescence quenching even at a high concentration of melatonin, making it an ideal nanocarrier for bioimaging and drug delivery.

DNA biodots based targeted theranostic nanomedicine for the imaging and treatment of non-small cell lung cancer.

The light absorption and emission characteristics of DNA biodots (DNA-BD), along with biocompatibility, give them a high potential for use in various medical applications, particularly in diagnostic purpose. DNA, under high pressure and temperature, condenses to form luminescent biodots. The objective of this research is to develop DNA-biodots (BD) loaded and cetuximab conjugated targeted theranostic liposomes of etoposide for lung cancer imaging and therapy. Theranostic liposomes were prepared by using the solvent injection method and characterized for their particle size, polydispersity, zeta potential, encapsulation efficiency, and pH-dependent in-vitro release, SEM, TEM AFM, EDX, and XRD. The t50% (time at which 50% of the drug releases from the preparation) of the formulations was pH-dependent, with a significant increase in the release at lower pH (5.5). To kill A549 adenocarcinoma cells, the etoposide (control) required significantly (p < 0.05) higher drug concentrations in comparison to non-targeted and; the non-targeted formulation required more concentrations in comparison to targeted liposomes. The in-vivo results demonstrated that CTX-TPGS decorated theranostic liposomes could be a promising carrier for lung theranostics due to their nano-size and selectivity towards EGFR overexpressed cells which provided an improved NSCLC targeted delivery of ETP in comparison to the non-targeted and control formulations.

Intracellular Delivery of Luciferase with Fluorescent Nanodiamonds for Dual-Modality Imaging of Human Stem Cells.

Delivering functional proteins (such as enzymes) into cells is important in various biological studies and is often accomplished indirectly by transfection with DNA or mRNA encoding recombinant proteins. However, the transfection efficiency of conventional plasmid methods is low for primary cells, which are crucial sources of cell therapy. Here, we present a new platform based on the use of fluorescent nanodiamond (FND) as a biocompatible nanocarrier to enable rapid, effective, and homogeneous labeling of human mesenchymal stem cells (MSCs) with luciferase for multiplex assays and ultrasensitive detection. More than 100 pg of FND and 100 million copies of firefly luciferase can be delivered into each MSC through endocytosis. Moreover, these endocytic luciferase molecules are catalytically active for hours, allowing the cells to be imaged and tracked in vitro as well as in vivo by both fluorescence and bioluminescence imaging. Our results demonstrate that luciferase-conjugated FNDs are useful as multifunctional labels of human stem cells for diverse theranostic applications.

Ultra-sensitive DNA sensing of a prostate-specific antigen based on 2D nanosheets in live cells.

Herein, we report ultra-sensitive sensing of a prostate-specific antigen (PSA), which is used as a biomarker to detect prostate cancer, using a molybdenum series (MoO3, MoS2, and MoSe2) of two-dimensional nanosheets (2D NSs). Moreover, the design of a 2D NS-based PSA aptamer sensor system was demonstrated based on a fluorescence turn-on mechanism in the presence of a target. The 2D NSs acted as an excellent sensing platform in which the PSA aptamer was adsorbed on the NSs and subsequent energy transfer between them led to fluorescence quenching of the aptamer. The detection limit of PSA was achieved to be 13 pM for MoO3 NSs, whereas the MoS2 and MoSe2 systems exhibited a detection limit of 72 and 157 pM, respectively. To the best of our knowledge, this is the first report on the ultra-sensitive detection of a 2D NS-based aptamer sensor. The in vitro bioimaging measurements were performed using confocal fluorescence microscopy. Herein, PSA detection was successfully demonstrated in human embryonic kidney 293T (HEK) live cells. Moreover, the MoO3, MoS2, and MoSe2 NSs exhibit excellent biocompatibility and low toxicity; thus, these 2D NSs can be used as a promising sensor platform to detect prostate cancer.