Stimuli-Responsive Prodrug Linkers That Simultaneously Release Cargo and Neutralize In Situ Generated (Aza)Quinone Methides.

Self-immolative linkers that use p-amino/hydroxy-benzyloxycarbonyl (PABC/PHBC) spacers are essential to the mechanism of many prodrugs. However, a highly reactive (aza)quinone methide is generated as a potential toxic byproduct. To remove the methide as it forms, we synthesized a series of novel tripartite prodrugs, comprising different triggers (nitro, amide, azide, boronate) and a PABC/PHBC-type self-immolative spacer with an integrated nucleophile (amine).

Phototruncation cell tracking with near-infrared photoimmunotherapy using heptamethine cyanine dye to visualise migratory dynamics of immune cells.

Background: Noninvasive in vivo cell tracking is valuable in understanding the mechanisms that enhance anti-cancer immunity. We have recently developed a new method called phototruncation-assisted cell tracking (PACT), that uses photoconvertible cell tracking technology to detect in vivo cell migration. This method has the advantages of not requiring genetic engineering of cells and employing tissue-penetrant near-infrared light.

Bluer Phototruncation: Retro-Diels-Alder of Heptamethine Cyanine to Trimethine Cyanine through an Allene Hydroperoxide Intermediate.

The photoconversion of heptamethine to pentamethine cyanines and of pentamethine to trimethine cyanines was recently reported. Here, we report mechanistic studies and initial experimental evidence for a previously unexplored 4-carbon truncation reaction that converts the simplest heptamethine cyanine to the corresponding trimethine cyanine. We propose a DFT-supported model describing a singlet oxygen (O)-mediated formation of an allene hydroperoxide intermediate and subsequent 4-carbon loss through a retro-Diels-Alder process.

Synthesis and Biological Evaluation of Aurachin D Analogues as Inhibitors of Cytochrome Oxidase.

A revised total synthesis of aurachin D (), an isoprenoid quinolone alkaloid that targets () cytochrome (cyt-) oxidase, was accomplished using an oxazoline ring-opening reaction. The ring opening enabled access to a range of electron-poor analogues, while electron-rich analogues could be prepared using the Conrad-Limpach reaction. The aryl-substituted and side-chain-modified aurachin D analogues were screened for inhibition of cyt- oxidase and growth inhibition of .

Structure-Activity Relationships of Antibody-Drug Conjugates: A Systematic Review of Chemistry on the Trastuzumab Scaffold.

Antibody-drug conjugates (ADCs) are a rapidly growing class of cancer therapeutics that seek to overcome the low therapeutic index of conventional cytotoxic agents. However, realizing this goal has been a significant challenge. ADCs comprise several independently modifiable components, including the antibody, payload, linker, and bioconjugation method.

Cyanine Phototruncation Enables Spatiotemporal Cell Labeling.

Photoconvertible tracking strategies assess the dynamic migration of cell populations. Here we develop hototruncation-ssisted ell racking (PACT) and apply it to evaluate the migration of immune cells into tumor-draining lymphatics. This method is enabled by a recently discovered cyanine photoconversion reaction that leads to the two-carbon truncation and consequent blue-shift of these commonly used probes.

SMA-BmobaSNO: an intelligent photoresponsive nitric oxide releasing polymer for drug nanoencapsulation and targeted delivery.

Nitric oxide (NO) is an important biological signalling molecule that acts to vasodilate blood vessels and change the permeability of the blood vessel wall. Due to these cardiovascular actions, co-administering NO with a therapeutic could enhance drug uptake. However current NO donors are not suitable for targeted drug delivery as they systemically release NO.

Ketone Incorporation Extends the Emission Properties of the Xanthene Scaffold Beyond 1000 nm.

Imaging in the shortwave-infrared region (SWIR, λ = 1000-2500 nm) has the potential to enable deep tissue imaging with high resolution. Critical to the development of these methods is the identification of low molecular weight, biologically compatible fluorescent probes that emit beyond 1000 nm. Exchanging the bridging oxygen atom on the xanthene scaffold (C10' position) with electron withdrawing groups has been shown to lead to significant redshifts in absorbance and emission.

Defining the Basis of Cyanine Phototruncation Enables a New Approach to Single-Molecule Localization Microscopy.

The light-promoted conversion of extensively used cyanine dyes to blue-shifted emissive products has been observed in various contexts. However, both the underlying mechanism and the species involved in this photoconversion reaction have remained elusive. Here we report that irradiation of heptamethine cyanines provides pentamethine cyanines, which, in turn, are photoconverted to trimethine cyanines.

Core remodeling leads to long wavelength fluoro-coumarins.

Low molecular weight, uncharged far-red and NIR dyes would be enabling for a range of imaging applications. Rational redesign of the coumarin scaffold leads to Fluoro-Coumarins (FCs), the lowest molecular weight dyes with emission maxima beyond 700, 800, and 900 nm. FCs display large Stokes shifts and high environmental sensitivity, with a 40-fold increase in emission intensity in hydrophobic solvents.

Photoblueing of organic dyes can cause artifacts in super-resolution microscopy.

Illumination of fluorophores can induce a loss of the ability to fluoresce, known as photobleaching. Interestingly, some fluorophores photoconvert to a blue-shifted fluorescent molecule as an intermediate on the photobleaching pathway, which can complicate multicolor fluorescence imaging, especially under the intense laser irradiation used in super-resolution fluorescence imaging. Here, we discuss the mechanisms of photoblueing of fluorophores and its impact on fluorescence imaging, and show how it can be prevented.

Conformationally restrained pentamethine cyanines and use in reductive single molecule localization microscopy.

Pentamethine cyanines are a class of far-red fluorophores that find extensive use in single-molecule localization microscopy (SMLM), as well as a broad range of other techniques. A drawback of this scaffold is its relatively low quantum yields, which is due to excited state deactivation via trans-to-cis chromophore isomerization. Here we describe a synthetic strategy to improve the photon output of these molecules.

Impact of Cyanine Conformational Restraint in the Near-Infrared Range.

Appending conformationally restraining ring systems to the cyanine chromophore creates exceptionally bright fluorophores in the visible range. Here, we report the application of this strategy in the near-infrared range through the preparation of the first restrained heptamethine indocyanine. Time-resolved absorption spectroscopy and fluorescence correlation spectroscopy verify that, unlike the corresponding parent unrestrained variant, the restrained molecule is not subject to photoisomerization.

Mechanistic Evaluation of Bioorthogonal Decaging with trans-Cyclooctene: The Effect of Fluorine Substituents on Aryl Azide Reactivity and Decaging from the 1,2,3-Triazoline.

Bioorthogonal prodrug activation/decaging strategies need to be selective, rapid and release the drug from the masking group upon activation. The rates of the 1,3-dipolar cycloaddition between a trans-cyclooctene (TCO) and a series of fluorine-substituted azido-PABC self-immolative spacers caging two model drugs, and subsequent release from the 1,2,3-triazoline are reported. As the number of fluorine substituents on the PABC linker increases from one to four, the rate of cycloaddition increases by almost one order of magnitude.

Stability, Kinetic, and Mechanistic Investigation of 1,8-Self-Immolative Cinnamyl Ether Spacers for Controlled Release of Phenols and Generation of Resonance and Inductively Stabilized Methides.

Three cinnamyl ether spacers (non-methyl, α-methyl, and γ-methyl) for caging of phenols have been synthesized and are physiologically stable. When triggered, the γ-methyl spacer releases phenols (pK 7.8 and 9.

Hypoxia Responsive Drug Delivery Systems in Tumor Therapy.

Hypoxia is a common characteristic of solid tumors. It is mainly determined by low levels of oxygen resulting from imperfect vascular networks supplying most tumors. In an attempt to improve the present chemotherapeutic treatment and reduce associated side effects, several prodrug strategies have been introduced to achieve hypoxia-specific delivery of cytotoxic anticancer agents.

Bioorthogonal prodrug activation driven by a strain-promoted 1,3-dipolar cycloaddition.

Due to the formation of hydrolysis-susceptible adducts, the 1,3-dipolar cycloaddition between an azide and strained -cyclooctene (TCO) has been disregarded in the field of bioorthogonal chemistry. We report a method which uses the instability of the adducts to our advantage in a prodrug activation strategy. The reaction of -cyclooctenol (TCO-OH) with a model prodrug resulted in a rapid 1,3-dipolar cycloaddition with second-order rates of 0.

Discovery and structure optimization of a series of isatin derivatives as Mycobacterium tuberculosis chorismate mutase inhibitors.

In this study, the crystal structure of the Mycobacterium tuberculosis (MTB) enzyme chorismate mutase (CM) bound to transition state analogue (PDB: 2FP2) was used as a framework for virtual screening of the BITS-Pilani in-house database (2500 compounds) to identify new scaffold. We identified isatin as novel small molecule MTB CM inhibitors; further twenty-four isatin derivatives were synthesized and evaluated in vitro for their ability to inhibit MTB CM, and activity against M. tuberculosis as steps towards the derivation of structure-activity relationships (SAR) and lead optimization.

Identification and structure-activity relationship study of carvacrol derivatives as Mycobacterium tuberculosis chorismate mutase inhibitors.

In the present study, we identified carvacrol, a major phenolic component of oregano oil as a novel small molecule inhibitor of Mycobacterium tuberculosis (MTB) chorismate mutase (CM) enzyme with IC50 of 1.06 ± 0.4 µM.

Preparation of fluoroalkenes via the Shapiro reaction: direct access to fluorinated peptidomimetics.

Fluoroalkenes represent a useful class of peptidomimetics with distinct biophysical properties. Current preparations of this functional group commonly provide mixtures of E- or Z-fluoroalkene diastereomers, and/or mixtures of nonfluorinated products. To directly access fluoroalkenes in good stereoselectivity, a Shapiro fluorination reaction was developed.