Synthesis and Biological Evaluation of Colchicine─Aryl/Alkyl Amine Hybrids as Potential Noncytotoxic Cholinesterase Inhibitors: Identification of SBN-284 as a Dual Inhibitor of Cholinesterases and NLRP3 Inflammasome.

Colchicine, one of the oldest anti-inflammatory natural products still used clinically, inhibits NF-κB signaling and NLRP3 inflammasome activation. Despite its cytotoxicity and narrow therapeutic range, colchicine continues to intrigue medicinal chemists exploring its anti-inflammatory potential. This study aimed to investigate the colchicine scaffold for its role in Alzheimer's disease by targeting neuroinflammation and cholinesterases.

Trilliumosides K and L, two novel steroidal saponins from rhizomes of , as potent anti-cancer agents targeting apoptosis in the A-549 cancer cell line.

Two novel steroidal saponins, trilliumosides K () and L (), were isolated from the rhizomes of led by bioactivity-guided phytochemical investigation along with seven known compounds: govanoside D (), protodioscin (), borassoside E (), 20-hydroxyecdysone (), 5,20-hydroxyecdysone (), govanic acid (), and diosgenin (). The structure of novel compounds 1-2 was established using analysis of spectroscopic data including 1D and 2D nuclear magnetic resonance (NMR) and high resolution mass spectrometry (HR-ESI-MS) data. All isolated compounds were evaluated for cytotoxic activity against a panel of human cancer cell lines.

Costunosides A-C: cytotoxic sesquiterpene lactones from the rhizomes of Falc.

Three new eudesmane type rare sesquiterpene lactone galactosides, costunosides A-C ( were isolated from the rhizomes of along with ten known compounds (). Costunosides A-C ( are the first example of naturally eudesmane glycosides containing a -galactopyranoside moiety. The structure and relative configurations of these compounds were established by comprehensive analysis of MS and, in particular 1D/2D NMR spectroscopic data.

Apoptotic Potential and Antitumor Efficacy of Trilliumoside A: A New Steroidal Saponin Isolated from Rhizomes of .

Natural product-derived molecules exhibit potential as anticancer agents. Trilliumoside A, a new steroidal saponin, was obtained from rhizomes of , and its anticancer activity was investigated in the presented study. Trilliumoside A was investigated in a panel of cell lines, and it exhibited promising cytotoxic activity on the A549 cells (human lung cancer cells) with an IC of 1.

Antifibrotic Agent Mediated Tumor Microenvironment Modulation and Improved Nanomedicine Delivery in Solid Tumor.

The unique physiology of tumors limits the efficacy of chemotherapeutics. In efforts to improve the effectiveness of the existing chemotherapy drugs, nanomedicine emerged as a new hope but proved inadequate due to the transport barriers present within the tumor tissues, which limits the potential of nanomedicine. Dense collagen networks in fibrotic tissues contribute to hindering the penetration of molecular- or nano-scale medicine through tumor interstitium.

In vitro and in vivo anticancer potential and molecular targets of the new colchicine analog IIIM-067.

Objective: The current study evaluated various new colchicine analogs for their anticancer activity and to study the primary mechanism of apoptosis and in vivo antitumor activity of the analogs with selective anticancer properties and minimal toxicity to normal cells.

Methods: Sulforhodamine B (SRB) assay was used to screen various colchicine analogs for their in vitro cytotoxicity. The effect of N-[(7S)-1,2,3-trimethoxy-9-oxo-10-(pyrrolidine-1-yl)5,6,7,9-tetrahydrobenzo[a] heptalene-7-yl] acetamide (IIIM-067) on clonogenicity, apoptotic induction, and invasiveness of A549 cells was determined using a clonogenic assay, scratch assay, and staining with 4',6-diamidino-2-phenylindole (DAPI) and annexin V/propidium iodide.

Gold nanoblackbodies mediated plasmonic photothermal cancer therapy for melanoma.

Gold nanoblackbodies (AuNBs)-mediated plasmonic photothermal cancer therapy was investigated through melanoma-bearing mice. Polydopamine-coated Au nanoclusters were synthesized, termed AuNBs and PEGylated AuNBs (AuNBs-PEG). The photothermal response of AuNBs-PEG was evaluated upon low-intensity broadband near-infrared irradiation (785/62 nm; 0.

Implication of methylselenocysteine in combination chemotherapy with gemcitabine for improved anticancer efficacy.

The limitations associated with cancer monotherapy including dose dependent toxicity and drug resistance can be addressed by combination chemotherapy. The combination of antineoplastic agents improves the cytotoxic activity in comparison to the single-agent based therapy in a synergistic or an additive mode by reducing tumor growth as well as metastatic ability. In the present investigation, we explored the potential of methylselenocysteine (MSC) in combination chemotherapy with gemcitabine (GEM).

Activation of lysosomal mediated cell death in the course of autophagy by mTORC1 inhibitor.

Lysosomal biogenesis plays a vital role in cell fate. Under certain conditions, excessive lysosomal biogenesis leads to susceptibility for lysosomal membrane permeabilization resulting in various pathological conditions including cell death. In cancer cells apoptosis machinery becomes dysregulated during the course of treatment, thus allows cancer cells to escape apoptosis.

A rohitukine derivative IIIM-290 induces p53 dependent mitochondrial apoptosis in acute lymphoblastic leukemia cells.

Rohitukine, a chromone alkaloid extracted from Dysoxylum binectariferum, has a propitious anticancer activity. Our previous study shows that a new Rohitukine derivative IIIM-290 restricts the growth of pancreatic cancer in vivo and in vitro. In the present findings, we report the mechanism of cell death induced by IIIM-290 in MOLT-4 cells (acute lymphoblastic leukemia) and its anticancer potential against various murine leukemic tumor models in vivo.

An improved synthesis of indanocine and antiproliferative activity of 2-benzylindanocine via microtubule destabilization.

Indanocine, a potent anticancer investigational drug of National Cancer Institute-USA, has been much discussed in recent years. Present communication aimed at total synthesis of indanocine and its close analogues. Total synthesis was improved by double yields than previously reported yields.

Novel Vitamin E TPGS based docetaxel nanovesicle formulation for its safe and effective parenteral delivery: Toxicological, pharmacokinetic and pharmacodynamic evaluation.

Docetaxel (DTX) is a highly lipophilic, BCS class IV drug with poor aqueous solubility (12.7 µg/mL). Presently, only injectable formulation is available in the market which uses a large amount of surfactant (Tween 80) and dehydrated alcohol as a solubilizer.

Antiproliferative activity of diarylnaphthylpyrrolidine derivative via dual target inhibition.

Breast cancer is the second leading cause of deaths in women globally. Present communication deals with design and synthesis of a few diarylnaphthyls as possible anti-breast cancer agents. Among the thirty three representatives with significant antiproliferative activity compounds 23 and 50 were quite efficacious against human breast cancer cells.

Binary and ternary solid dispersions of an anticancer preclinical lead, IIIM-290: In vitro and in vivo studies.

The objective of this study was to formulate an anticancer preclinical lead, IIIM-290, loaded in solid dispersions to enhance its solubility, dissolution, and oral pharmacokinetics. IIIM-290 is an in-house preclinical anticancer lead prepared by semisynthetic modification of the natural product rohitukine. It is an orally bioavailable Cdk inhibitor showing efficacy in xenograft models of pancreatic, colon and leukemia cancer.

Gemcitabine and betulinic acid co-encapsulated PLGA-PEG polymer nanoparticles for improved efficacy of cancer chemotherapy.

The present study demonstrated the development of gemcitabine and betulinic acid co-encapsulated PLGA-PEG polymer nanoparticles for enhancing the chemotherapeutic response. This combinatorial PLGA-PEG nanoparticle was formulated using double emulsion and had size <200 nm. The developed nanoparticles were characterized using dynamic light scattering and transmission electron microscopy for their size and shape, respectively.

Synthesis and Investigation of the Role of Benzopyran Dihydropyrimidinone Hybrids in Cell Proliferation, Migration and Tumor Growth.

Background: Cancer is the second leading cause of mortality worldwide after heart diseases, and lung cancer is the topmost cause of all cancer-related deaths in both sexes. Dihydropyrimidinones (DHPMs) are medicinally important class of molecules with diverse pharmacological activities including anticancer activity. The present study focuses on the molecular hybridization of novel Benzopyran with Dihydropyrimidinone and evaluation of the resulting hybrids for cancer cell proliferation, migration and tumor growth.

Antitumour, acute toxicity and molecular modeling studies of 4-(pyridin-4-yl)-6-(thiophen-2-yl) pyrimidin-2(1H)-one against Ehrlich ascites carcinoma and sarcoma-180.

In an effort to discover an effective and selective antitumour agent, synthesis and anti-cancer potential of 4-(pyridin-4-yl)-6-(thiophen-2-yl) pyrimidin-2(1)-one (), which has been reported earlier by us with significant cytotoxicity towards MiaPaCa-2 malignant cells, with an IC value of 1.95 μM and was found to instigate apoptosis. In the present study, the antitumour efficacy of was investigated on Ehrlich ascites tumour (EAT, solid), Sarcoma 180 (solid) tumour and Ehrlich ascites carcinoma.

Antiproliferative efficacy of curcumin mimics through microtubule destabilization.

Curcumin possesses an attractive chemical structure with highly conjugated diferuloylmethane core. Curcumin mimics have been designed and prepared with an additional bridged phenyl ring in conjugation. Fourteen diverse analogues were evaluated against a panel of human cancer cell lines.

Discovery and Preclinical Development of IIIM-290, an Orally Active Potent Cyclin-Dependent Kinase Inhibitor.

Rohitukine (1), a chromone alkaloid isolated from Indian medicinal plant Dysoxylum binectariferum, has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via intravenous route. With the objective to address the oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative IIIM-290 (11d) showed strong inhibition of Cdk-9/T1 (IC 1.

Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model.

In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ∼33 in comparison to reported leads.

4-aryl/heteroaryl-4H-fused Pyrans as Anti-proliferative Agents: Design, Synthesis and Biological Evaluation.

Aims: The current study is focused on the design and synthesis of 4-aryl/heteroaryl-4H-fused pyrans as anti-proliferative agents. All the synthesized molecules were screened against a panel of human carcinoma cell lines.

Description: Significant inhibition was exhibited by the compounds against HCT-116 (Colon) and PC-3 (Prostate) cell lines while A-549 (Lung) cell lines, MiaPaCa-2 (Pancreatic) cell lines and HL-60 (Leukemia Cancer) cell lines were almost resistant to the exposure of the test compounds.

Development and characterization of hyaluronic acid modified PLGA based nanoparticles for improved efficacy of cisplatin in solid tumor.

Cisplatin is a potent and widely used chemotherapeutic agent to treat a variety of tumors. However, its clinical use is associated with undesirable side effects and acquired resistance to cisplatin. In this study, cisplatin loaded hyaluronic acid (HA) functionalized poly (lactic-co-glycolic acid)-poly (ethylene glycol) nanoparticles (CP-HA-PLGA-PEG-NPs) were fabricated using double emulsion solvent evaporation method to target CD44 receptor expressed on cancerous cells.

Development and evaluation of long-circulating nanoparticles loaded with betulinic acid for improved anti-tumor efficacy.

The clinical application of betulinic acid (BA), a natural pentacyclic triterpenoid with promising antitumor activity, is hampered due to its extremely poor water solubility and relatively short half-life in the systemic circulation. In order to address these issues, herein, we developed betulinic acid loaded polylactide-co-glycolide- monomethoxy polyethylene glycol nanoparticles (PLGA-mPEG NPs). The PLGA-mPEG co-polymer was synthesized and characterized using NMR and FT-IR.

A marine sponge alkaloid derivative 4-chloro fascaplysin inhibits tumor growth and VEGF mediated angiogenesis by disrupting PI3K/Akt/mTOR signaling cascade.

Tumor angiogenesis and PI3K/Akt/mTOR pathway are two major molecular objectives for the treatment and management of breast cancer. Here we first time report the molecular mechanism of a marine sponge alkaloid derivative 4-chloro fascapysin (4-CF) for its anticancer and antiangiogenesis potential. It simultaneously targets multiple cancer and angiogenesis dynamics, such as proliferation, chemotaxis cell migration, and invasion, growth factors signaling cascade, autophagy and apoptosis in HUVEC and MDAMB-231 breast cancer cells.