Investigation of Trimethylenemethane Cyclopentyl-Annulations as a Strategy to Obtain a Functionalized Angular Triquinane Skeleton.

The angular triquinane carbocyclic ring system is a component of many natural products found in numerous terrestrial and marine plants. A strategy for the synthesis of functionalized angular triquinanes utilizing two trimethylenemethane (TMM)-based [3+2] cycloaddition reactions is presented. This synthetic strategy employs the intermolecular dyil-trapping reaction to give eventual access to the bicyclo[3.

The Aryl Hydrocarbon Receptor Undergoes Chaperone-Mediated Autophagy in Triple-Negative Breast Cancer Cells.

The aryl hydrocarbon receptor (AHR) is a ligand-activated signaling molecule expressed in many cell types, including triple-negative and non-triple-negative breast cancer cells. It affects breast cancer growth and crosstalk with estrogen receptor signaling. Normally, this receptor is degraded shortly after ligand activation via the 26S proteasome.

Pharmacological Inhibition of CDK8 in Triple-Negative Breast Cancer Cell Line MDA-MB-468 Increases E2F1 Protein, Induces Phosphorylation of STAT3 and Apoptosis.

Cyclin-dependent kinase 8 (CDK8) has been identified as a colon cancer oncogene. Since this initial observation, CDK8 has been implicated as a potential driver of other cancers including acute myelogenous leukemia (AML) and some breast cancers. Here, we observed different biological responses to CDK8 inhibition among colon cancer cell lines and the triple-negative breast cancer (TNBC) cell line MDA-MB-468.

Preliminary in vitro and in vivo investigation of a potent platelet derived growth factor receptor (PDGFR) family kinase inhibitor.

Aberrant expression of wild-type and mutant forms of the platelet-derived growth factor receptor (PDGFR) family of receptor tyrosine kinases has been implicated in various oncologic indications such as leukemias, gliomas, and soft tissue sarcomas. Clinically used kinase inhibitors imatinib and sunitinib are potent inhibitors of wild-type PDGFR family members, but show reduced binding to mutant forms. Here we describe compound 5 which binds to both wild-type and oncogenic mutant forms of PDGFR family members, and demonstrates both cellular and in vivo activity.

Molecular docking and synthesis of novel quinazoline analogues as inhibitors of transcription factors NF-κB activation and their anti-cancer activities.

NF-kB is a transcription factor protein complex that can be found in almost all animal cell types and is a key player in some cancers and inflammatory responses. It can enhance the proliferation rate, reduce apoptosis, as well as creating more blood flow to ensure the survival of cancer, thus blocking the NF-kB pathway has potential therapeutic benefit. We designed a series of compounds based on a quinazoline scaffold pharmacophore model which may have high binding affinity with the p50 subunit of NF-kB.

Novel design and synthesis of modified structure of carvedilol.

β-adrenergic blocking agents have been in use for nearly 40 years. β-blockers have been more thoroughly studied in the past twenty years as they have become commonly prescribed to heart failure patients. The class of β-blockers has grown considerably and has many pharmaceutical applications in patients with heart failure.

Novel integrin-targeted binding-triggered drug delivery system for methotrexate.

Purpose: To design a binding-induced conformation change drug delivery system for integrin-targeted delivery of methotrexate and prove the feasibility of using hairpin peptide structure for binding triggered drug delivery.

Methods: Methotrexate prodrugs were synthesized using solid phase peptide synthesis techniques by conjugating methotrexate to Arg-Gly-Asp (RGD) or a hairpin peptide, RWQYV(D)PGKFTVQRGD (hairpin-RGD). Levels of integrin α(V)β(3) in HUVEC were up-regulated using adenoviral system and knocked down using siRNA.

Discovery, synthesis, and investigation of the antitumor activity of novel piperazinylpyrimidine derivatives.

Protein kinases play several pertinent roles in cell proliferation, and targeting these proteins has been shown to be a successful strategy toward controlling different malignancies. Despite the great discovery stories during the last two decades, there is still a demand for anticancer small molecules with the potential of being selective on both the protein kinase and/or the cellular level. A series of novel piperazinylpyrimidine compounds were synthesized and tested for their potential to selectively inhibit the growth of certain tumor cell lines included within the NCI-60 cell line panel.

Anti-tumor pyrimidinylpiperazines bind to the prosurvival Bcl-2 protein family member Bcl-XL.

Overexpression of prosurvival or underexpression of pro-death Bcl-2 family proteins can lead to cancer cell resistance to chemotherapy and radiation treatment. Inhibition of the prosurvival Bcl-2 family proteins has become a strategy for cancer therapy and inhibitors are currently being evaluated in the clinic both as single agents and in combination with established drugs. Here we describe the design, synthesis, and evaluation of pyrimidylpiperazines that were discovered to be inhibitors of the prosurvival Bcl-2 protein family member Bcl-XL.

Preliminary studies of 3,4-dichloroaniline amides as antiparasitic agents: structure-activity analysis of a compound library in vitro against Trichomonas vaginalis.

Trichomonas vaginalis, a human-infectious protozoan, can display resistance to treatment by metronidazole. A library of 3,4-dichloroaniline amides based on propanil, an herbicide, has been synthesized and screened to test susceptibility to these analogs. From this preliminary study, the most effective compound 15, inhibits growth of the organism by 66% and 69% on the two strains tested, T1 and G3, respectively.

Cell recognition enhanced enzyme hydrolysis of a model peptide-drug conjugate.

A model peptide-drug conjugate designed upon a beta-hairpin peptide with the alpha4beta1 integrin recognition sequence LDV appended to the N-terminus and a fluorescent model drug appended to the C-terminus. This model recognizes and binds to alpha4beta1 expressing cells and displays an enhanced rate of enzyme catalyzed hydrolytic model drug release in the presence of the cells compared to the rate in the absence of cells. The present work suggests that peptide-drug conjugate conformation change due to receptor binding may be a viable approach to targeted drug release.

Cyclic modular beta-sheets.

The development of peptide beta-hairpins is problematic, because folding depends on the amino acid sequence and changes to the sequence can significantly decrease folding. Robust beta-hairpins that can tolerate such changes are attractive tools for studying interactions involving protein beta-sheets and developing inhibitors of these interactions. This paper introduces a new class of peptide models of protein beta-sheets that addresses the problem of separating folding from the sequence.

Thiazolidinedione anti-cancer activity: Is inhibition of microtubule assembly implicated?

An hypothesis is presented which seeks to explain the anti-cancer activity of thiazolidinediones (TZDs), a class of drugs currently used to treat type 2 diabetes mellitus. Empirical data from the scientific literature is used to support the hypothesis that TZDs are inhibitors of microtubule assembly. The similarities between the affects of TZDs on cellular processes and known inhibitors of tubulin polymerization are identified.