Drug-Linker Constructs Bearing Unique Dual-Mechanism Tubulin Binding Payloads Tethered through Cleavable and Non-Cleavable Linkers.

Antibody-drug conjugates (ADCs) have advanced as a mainstay among the most promising cancer therapeutics, offering enhanced antigen targeting and encompassing wide diversity in their linker and payload components. Small-molecule inhibitors of tubulin polymerization have found success as payloads in FDA approved ADCs and represent further promise in next-generation, pre-clinical and developmental ADCs. Unique dual-mechanism payloads (previously designed and synthesized in our laboratories) function as both potent antiproliferative agents and promising vascular disrupting agents capable of imparting selective and effective damage to tumor-associated microvessels.

An antibacterial membrane based on Janus bacterial cellulose with nano-sized copper oxide through polydopamine conjugation for infectious wound healing.

Bacterial cellulose (BC) produced by Acetobacter xylinum has great advantages in wound dressing. However, the structural limitation under static culture, and lack of antibacterial properties restrict its application, especially for infectious wound healing. The present study reported an original wound dressing, which was composed of a Janus BC membrane with antibacterial nano-sized copper oxide (CuO) through polydopamine (PDA) conjugation to promote wound healing under infectious condition.

Piptide Chemotypes for Perturbation of the Interaction of Urokinase with Its Receptor.

Only a few small molecules that disrupt the uPA and uPA receptor (uPAR) interaction have been discovered despite decades of research in the area, and none have been approved in clinical trials. Research reported here features two new ways of considering the problem of discovering small molecules to disrupt uPA•uPAR, specifically in terms of chemotype design and method of evaluation. Chemotypes used in this work are (Arancillo .

Apatite nanosheets inhibit initial smooth muscle cell proliferation by damaging cell membrane.

Understanding how nanostructured coatings interact with cells is related to how they manipulate cell behaviors and is therefore critical for designing better biomaterials. The apatite nanosheets were deposited on metallic substrates via biomimetic precipitation. Cell viability of apatite nanosheets towards to smooth muscle cells (SMCs) were investigated, and the underlying mechanism was proposed.

Small molecules targeting the NEDD8·NAE protein-protein interaction.

Ubiquitination is a major controller of protein homeostasis in cells. Some ubiquitination pathways are modulated by a NEDDylation cascade, that also features E1 - 3 enzymes. The E1 enzyme in the NEDDylation cascade involves a protein-protein interaction (PPI) between NEDD8 (similar to ubiquitin) and NAE (NEDD8 Activating Enzyme).

Unconventional Secondary Structure Mimics: Ladder-Rungs.

Secondary structures tend to be recognizable because they have repeating structural motifs, but mimicry of these does not have to follow such well-defined patterns. Bioinformatics studies to match side-chain orientations of a novel hydantoin triazole chemotype (1) to protein-protein interfaces revealed it tends to align well across parallel and antiparallel sheets, like rungs on a ladder. One set of these overlays was observed for the protein-protein interaction uPA⋅uPAR.

Patterned iridium oxide film as neural electrode interface: Biocompatibility and improved neurite outgrowth with electrical stimulation.

Iridium (Ir) thin film was deposited on patterned titanium substrate by direct-current (DC) magnetron sputtering, and then activated in sulfuric acid (HSO) through repetitive potential sweeps to form iridium oxide (IrO) as neural electrode interface. The resultant IrO film showed a porous and open morphology with aligned microstructure, exhibited superior electrochemical performance and excellent stability. The IrO film supported neural stem cells (NSCs) attachment, proliferation and improved processes without causing toxicity.

Protein labelling and albumin binding characteristics of the near-IR Cy7 fluorophore, QuatCy.

Free cysteine residues react with QuatCy 1, by simply mixing the protein and dye in aqueous buffer at 37 °C. Another dye, MHI-148, can be used for a similar labelling protocol, but QuatCy reacts faster with all proteins studied, except albumin; it emerges here that this is because MHI-148 instantly forms of a non-covalent complex with albumin, but QuatCy does not. Labelling with QuatCy has advantages insofar as it is over five times brighter, and much more photostable, than MHI-148, and combination labelling with this dye pair will allow multiplexing in the near-IR region.

Correlations between secondary structure- and protein-protein interface-mimicry: the interface mimicry hypothesis.

An active segment of the research community designing small molecules ("minimalist mimics" of peptide fragments) to interfere with protein-protein interactions have based their studies on an implicit hypothesis. Here we refer to this as the Secondary Structure Hypothesis, that might be defined as, "If a small molecule can orient amino acid side-chains in directions that resemble side-chains of the parent secondary structure at the interface, then that small molecule is a candidate to perturb the protein-protein interaction". Rigorous tests of this hypothesis require co-crystallization of minimalist mimics with protein receptors, and comparison of the bound conformations with the interface secondary structures they were designed to resemble.

Design criteria for minimalist mimics of protein-protein interface segments.

Small molecules that can interrupt or inhibit protein-protein interactions (PPIs) are valuable as probes in chemical biology and medicinal chemistry, but they are also notoriously difficult to develop. Design of non-peptidic small molecules that mimic amino acid side-chain interactions in PPIs ("minimalist mimics") is seen as a way to fast track discovery of PPI inhibitors. However, there has been little comment on general design criteria for minimalist mimics, even though such guidelines could steer construction of libraries to screen against multiple PPI targets.

Site-Specific Labeling of Proteins with Near-IR Heptamethine Cyanine Dyes.

Convenient labeling of proteins is important for observing its function under physiological conditions. In tissues particularly, heptamethine cyanine dyes (Cy-7) are valuable because they absorb in the near-infrared (NIR) region (750⁻900 nm) where light penetration is maximal. In this work, we found Cy-7 dyes with a -Cl functionality covalently binding to proteins with free Cys residues under physiological conditions (aqueous environments, at near neutral pH, and 37 °C).

On the Mechanisms of Uptake of Tumor-Seeking Cyanine Dyes.

Molecular entities that localize in tumor tissue are clinically important for targeted delivery of diagnostic, imaging, and therapeutic reagents. Often these targeting entities are designed for specific receptors (e.g.

Design, synthesis, and biological evaluation of water-soluble amino acid prodrug conjugates derived from combretastatin, dihydronaphthalene, and benzosuberene-based parent vascular disrupting agents.

Targeting tumor vasculature represents an intriguing therapeutic strategy in the treatment of cancer. In an effort to discover new vascular disrupting agents with improved water solubility and potentially greater bioavailability, various amino acid prodrug conjugates (AAPCs) of potent amino combretastatin, amino dihydronaphthalene, and amino benzosuberene analogs were synthesized along with their corresponding water-soluble hydrochloride salts. These compounds were evaluated for their ability to inhibit tubulin polymerization and for their cytotoxicity against selected human cancer cell lines.

Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization.

The discovery of 3-methoxy-9-(30,40,50-trimethoxyphenyl)-6,7-dihydro-5H-benzo[7]annulen-4-ol (a benzosuberene-based analogue referred to as KGP18) was originally inspired by the natural products colchicine and combretastatin A-4 (CA4). The relative structural simplicity and ease of synthesis of KGP18, coupled with its potent biological activity as an inhibitor of tubulin polymerization and its cytotoxicity (in vitro) against human cancer cell lines, has resulted in studies focused on new analogue design and synthesis. Our goal was to probe the relationship of structure to function in this class of anticancer agents.

Synthesis of structurally diverse benzosuberene analogues and their biological evaluation as anti-cancer agents.

Diversely functionalized, fused aryl-alkyl ring systems hold a prominent position as well-established molecular frameworks for a variety of anti-cancer agents. The benzosuberene (6,7 fused, also referred to as dihydro-5H-benzo[7]annulene and benzocycloheptene) ring system has emerged as a valuable molecular core component for the development of inhibitors of tubulin assembly, which function as antiproliferative anti-cancer agents and, in certain cases, as vascular disrupting agents (VDAs). Both a phenolic-based analogue (known as KGP18, compound 39) and its corresponding amine-based congener (referred to as KGP156, compound 45), which demonstrate strong inhibition of tubulin assembly (low micromolar range) and potent cytotoxicity (picomolar range for KGP18 and nanomolar range for KGP156) are noteworthy examples of such benzosuberene-based compounds.