A series of 1H-imidazo [4,5-f][1,10] phenanthroline derivatives functionalized at 2-position with chiral, and conformationally flexible polyhydroxy alkyl chains derived from carbohydrates (alditol-based imidazophenanthrolines, aldo-IPs) is presented herein. These novel glycomimetics showed relevant and differential cytotoxic activity against several cultured tumor cell lines (PC3, HeLa and HT-29), dependent on the nature and stereochemistry of the polyhydroxy alkyl chain. The mannose-based aldo-IP demonstrated the higher cytotoxicity in the series, substantially better than cisplatin metallo-drug in all cell lines tested, and better than G-quadruplex ligand 360A in HeLa and HT29 cells. Cell cycle experiments and Annexin V-PI assays revealed that aldo-IPs induce apoptosis in HeLa cells. Initial study of DNA interactions by DNA FRET melting assays proved that the aldo-IPs produce only a slight thermal stabilization of DNA secondary structures, more pronounced in the case of quadruplex DNA. Viscosity titrations with CT dsDNA suggest that the compounds behave as DNA groove binders, whereas equilibrium dialysis assays showed that the compounds bind CT with Ka values in the range 104-105 M-1. The aldo-IP derivatives were obtained with synthetically useful yields through a feasible one-pot multistep process, by aerobic oxidative cyclization of 1,10-phenanthroline-5,6-diamine with a selection of unprotected aldoses using (NH4)2SO4 as promoter.

Modified nucleotides are ubiquitous with RNAs, also in contact with drugs that target the ribosome. Whether this represents a stabilization of the drug-ribosome complex, thus affecting the drug\'s affinity and possibly also intrinsic efficacy, remains an open question, however. The challenge of answering this question has been taken here with the only human-ribosome-targeting small-molecule currently in clinical use, the antitumor plant alkaloid homoharringtonine (HHT). The approach consisted in dissecting HHT-nucleotide interaction energies from QM-MM simulations in explicit water. What emerged is a network of mostly weak interactions of the large, branched HHT with standard nucleotides and a single modified nucleotide, out of the four ones present at PCT\'s A site. This is unlike the case of the small, compact marine antitumor alkaloid agelastatin A, which displays only a few, albeit strong, interactions with site-A ribosome nucleotides. This should aid tailoring drugs targeting the ribosome.

A novel series of phthalimide derivatives was synthesized and evaluated for in vitro antitumor activity against six human cancer cell lines; HepG-2, HCT-116, MCF-7, Hep2, PC3 and Hela.The obtained results revealed that compound 32 was the most potent antitumor, while compounds 33, 22 and 24 showed strong activity against all tested cell lines. Further biological evaluation of the most active compounds was done and their in vitro EGFR-TK inhibition was tested, and the results came in accordance with the results of antitumor testing, where 32 displayed promising inhibitory activity (IC50 = 0.065 µM) compared to the standard drug erlotinib (IC50 = 0.067 µM). In addition, compounds 48, 22, 28 and 19 showed strong inhibitory activity (IC50 = 0.089, 0.093, 0.147 and 0.152 µM respectively). Cell cycle analysis was conducted and the results revealed that 32 induced cell cycle arrest on Hela and MCF-7 at G0-G1 phase and Pre-G1 phase causing cell death mainly via apoptosis. Additionally, in vivo antitumor screening revealed that 32 reduced both body weight and tumor volume in solid tumor utilizing Ehrlich ascites carcinoma (EAC) animal model. Molecular modeling study showed that 32 and 48 have the highest affinity for binding with the active site of EGFR-TK with docking score comparable to erlotinib. Compounds 32 and 48 could be used as template models for further optimization.

This study describes the preparation of nanoparticles derived from bovine serum albumin (BSA) in comparison with the formation of nanoparticles composed of human serum albumin (HSA), when the same preparation procedure was used in both cases. To obtain protein nanoparticles, the method of desolvation with ethanol was employed, followed by the stabilization with urea and cysteine. It was shown that, upon transition from HSA to BSA, the particles with smaller sizes and with a narrower polydispersity were formed. The possibility of the immobilization of the antitumor drug hydroxyurea in such protein nanoparticles by adsorption and inclusion methods has been shown. The drug release profile from the polymer matrix was established.

The limited success and side effects of the current chemotherapeutic strategies against colorectal cancer (CRC), the third most common cancer worldwide, demand an assay with new drugs. The prominent antitumor activities displayed by the bengamides (Ben), a family of natural products isolated from marine sponges of the Jaspidae family, were explored and investigated as a new option to improve CRC treatment. To this end, two potent bengamide analogues, Ben I (5) and Ben V (10), were selected for this study, for which they were synthesized according to a new synthetic strategy recently developed in our laboratories. Their antitumor effects were analyzed in human and mouse colon cell lines, using cell cycle analysis and antiproliferative assays. In addition, the toxicity of the selected analogues was tested in human blood cells. These biological studies revealed that Ben I and V produced a significant decrease in CRC cell proliferation and induced a significant cell cycle alteration with a greater antiproliferative effect on tumor cell lines than normal cells. Interestingly, no toxicity effects were detected in blood cells for both compounds. All these biological results render the bengamide analogues Ben I and Ben V as promising antitumoral agents for the treatment of CRC.

An intramolecular Diels-Alder (IMDA) reaction efficiently accelerated by Schreiner\'s thiourea is reported, to build a functionalized cytochalasin scaffold (periconiasin series) for biological purposes. DFT calculation highlighted a unique multidentate cooperative hydrogen bonding in this catalysis. The deprotection end game afforded a collection of diverse structures and showed the peculiar reactivity of the Diels-Alder cycloadducts upon functionalization. Biological studies revealed strong cytotoxicity of a few compounds on breast cancer cell lines while actin polymerization is preserved.

In a continuing search for curcuminoid (CUR) compounds with antitumor activity, a novel series of heterocyclic CUR-BF2 adducts and CUR compounds based on indole, benzothiophene, and benzofuran along with their aryl pyrazoles were synthesized. Computational docking studies were performed to compare binding efficiency to target proteins involved in specific cancers, namely HER2, proteasome, VEGFR, BRAF, and Bcl-2, versus known inhibitor drugs. The majority presented very good binding affinities, similar to, and even more favorable than those of known inhibitors. The indole-based CUR-BF2 and CUR compounds and their bis-thiocyanato derivatives exhibited high anti-proliferative and apoptotic activity by in vitro bioassays against a panel of 60 cancer cell lines, more specifically against multiple myeloma (MM) cell lines (KMS11, MM1.S, and RPMI-8226) with significantly lower IC50 values versus healthy PBMC cells; they also exhibited higher anti-proliferative activity in human colorectal cancer cells (HCT116, HT29, DLD-1, RKO, SW837, and Caco2) than the parent curcumin, while showing notably lower cytotoxicity in normal colon cells (CCD112CoN and CCD841CoN).

BACKGROUND: One approach to identify patients who meet specific eligibility criteria for target-based clinical trials is to use patient and tumor registries to prescreen patient populations.
OBJECTIVE: Here we demonstrate that the Total Cancer Care (TCC) Protocol, an ongoing, observational study, may provide a solution for rapidly identifying patients with CD30-positive tumors eligible for CD30-targeted therapies such as brentuximab vedotin.
METHODS: The TCC patient gene expression profiling database was retrospectively screened for CD30 gene expression determined using HuRSTA-2a520709 Affymetrix arrays (GPL15048). Banked tumor tissue samples were used to determine CD30 protein expression by semiquantitative immunohistochemistry. Statistical comparisons of Z- and H-scores were performed using R statistical software (The R Foundation), and the predictive value, accuracy, sensitivity, and specificity of CD30 gene expression versus protein expression was estimated.
RESULTS: As of March 2015, 120,887 patients have consented to the institutional review board-approved TCC Protocol. A total of 39,157 fresh frozen tumor specimens have been collected, from which over 14,000 samples have gene expression data available. CD30 RNA was expressed in a number of solid tumors; the highest median CD30 RNA expression was observed in primary tumors from lymph node, soft tissue (many sarcomas), lung, skin, and esophagus (median Z-scores 1.011, 0.399, 0.202, 0.152, and 1.011, respectively). High level CD30 gene expression significantly enriches for CD30-positive protein expression in breast, lung, skin, and ovarian cancer; accuracy ranged from 72% to 79%, sensitivity from 75% to 100%, specificity from 70% to 76%, positive predictive value from 20% to 40%, and negative predictive value from 95% to 100%.
CONCLUSIONS: The TCC gene expression profiling database guided tissue selection that enriched for CD30 protein expression in a number of solid tumor types. Such an approach may improve screening efficiency for enrolling patients into biomarker-based clinical trials.

A series of 12 analogues of the Cer transfer protein (CERT) antagonist HPA-12 with long aliphatic chains were prepared as their (1R,3S)-syn and (1R,3R)-anti stereoisomers from pivotal chiral oxoamino acids. The enantioselective access to these intermediates as well as their ensuing transformation relied on a practical crystallization-induced asymmetric transformation (CIAT) process. Sonogashira coupling followed by triple bond reduction and thiophene ring hydrodesulfurization (HDS) into the corresponding alkane moieties was then implemented to complete the synthetic routes delivering the targeted HPA-12 analogues in concise 4- to 6-step reaction sequences. Ten compounds were evaluated regarding their ability to bind to the CERT START domain by using the recently developed time-resolved FRET-based homogeneous (HTR-FRET) binding assay. The introduction of a lipophilic appendage on the phenyl moiety led to an overall 10- to 1000-fold enhancement of the protein binding, with the highest effect being observed for a n-hexyl residue in the meta position. The importance of the phenyl ring for the activity was indicated by the reduced potency of the 3-deoxyphytoceramide aliphatic analogues. The 1,3-syn stereoisomers were systematically more potent than their 1,3-anti analogues. In silico studies were used to rationalized these trends, leading to a model of protein recognition coherent with the stronger binding of (1R,3S)-syn HPAs.

As a continuous effort to develop novel antitumor agents, a new series of forty-five 2-phenol-4-aryl-6-chlorophenyl pyridine compounds were synthesized and evaluated for cytotoxicity against four different human cancer cell lines (DU145, HCT15, T47D, and HeLa), and topoisomerase I and II inhibitory activity. Several compounds (10-15, 20, 22, 24, 28, 42, and 49) displayed strong to moderate dual topoisomerase I and II inhibitory activity at 100 μM. It was observed that hydroxyl and chlorine moiety at meta or para position of phenyl ring is favorable for dual topoisomerase inhibitory activity and cytotoxicity. Most of the compounds displayed stronger cytotoxicities than those of all positive controls against the HCT15 and T47D cell lines. For investigation of the structure-activity relationships, a 3D-QSAR analysis using the method of comparative molecular field analysis (CoMFA) was performed. The generated 3D contour maps can be used for further rational design of novel terpyridine derivatives as highly selective and potent cytotoxic agents.