Stepwise optimization of tumor-targeted dual-action platinum(iv)-gemcitabine prodrugs.

While platinum-based chemotherapeutic agents have established themselves as indispensable components of anticancer therapy, they are accompanied by a variety of side effects and the rapid occurrence of drug resistance. A promising strategy to address these challenges is the use of platinum(iv) prodrugs, which remain inert until they reach the tumor tissue, thereby mitigating detrimental effects on healthy cells. Typically, platinum drugs are part of combination therapy settings.

Time/frequency-domain characterization of a mid-IR DFG frequency comb via two-photon and heterodyne detection.

Mid-infrared frequency combs are nowadays well-appreciated sources for spectroscopy and frequency metrology. Here, a comprehensive approach for characterizing a difference-frequency-generated mid-infrared frequency comb (DFG-comb) both in the time and in the frequency domain is presented. An autocorrelation scheme exploiting mid-infrared two-photon detection is used for characterizing the pulse width and to verify the optimal compression of the generated pulses reaching a pulse duration (FWHM) as low as 196 fs.

Insertion of (Bioactive) Equatorial Ligands into Platinum(IV) Complexes.

Platinum(IV) prodrugs are highly interesting alternatives to platinum(II) anticancer therapeutics due to their increased tumor selectivity and reduced side effects. In contrast to the established theory, we recently observed that the equatorial ligand(s) of e.g.

Tumor-targeted dual-action NSAID-platinum(iv) anticancer prodrugs.

Platinum(iv) prodrugs are a promising class of anticancer agents designed to overcome the limitations of conventional platinum(ii) therapeutics. In this work, we present oxaliplatin(iv)-based complexes, which upon reduction, release acetylsalicylic acid (aspirin), known for its antitumor activity against colon cancer and currently investigated in combination with oxaliplatin in a phase III clinical study. Comparison with a recently reported cisplatin analog (asplatin) revealed a massive increase in reduction stability for the oxaliplatin complex in mouse serum.

A platinum(IV) prodrug strategy to overcome glutathione-based oxaliplatin resistance.

Clinical efficacy of oxaliplatin is frequently limited by severe adverse effects and therapy resistance. Acquired insensitivity to oxaliplatin is, at least in part, associated with elevated levels of glutathione (GSH). In this study we report on an oxaliplatin-based platinum(IV) prodrug, which releases L-buthionine-S,R-sulfoximine (BSO), an inhibitor of glutamate-cysteine ligase, the rate-limiting enzyme in GSH biosynthesis.

Structure-Activity Relationships of Triple-Action Platinum(IV) Prodrugs with Albumin-Binding Properties and Immunomodulating Ligands.

Chemotherapy with platinum complexes is essential for clinical anticancer therapy. However, due to side effects and drug resistance, further drug improvement is urgently needed. Herein, we report on triple-action platinum(IV) prodrugs, which, in addition to tumor targeting maleimide-mediated albumin binding, release the immunomodulatory ligand 1-methyl-d-tryptophan (1-MDT).

Improving the Stability of Maleimide-Thiol Conjugation for Drug Targeting.

Maleimides are essential compounds for drug conjugation reactions via thiols to antibodies, peptides and other targeting units. However, one main drawback is the occurrence of thiol exchange reactions with, for example, glutathione resulting in loss of the targeting ability. A new strategy to overcome such retro-Michael exchange processes of maleimide-thiol conjugates by stabilization of the thiosuccinimide via a transcyclization reaction is presented.

High-resolution resonance-enhanced multiphoton photoelectron circular dichroism.

Photoelectron circular dichroism (PECD) is a highly sensitive enantiospecific spectroscopy for studying chiral molecules in the gas phase using either single-photon ionization or multiphoton ionization. In the short pulse limit investigated with femtosecond lasers, resonance-enhanced multiphoton ionization (REMPI) is rather instantaneous and typically occurs simultaneously via more than one vibrational or electronic intermediate state due to limited frequency resolution. In contrast, vibrational resolution in the REMPI spectrum can be achieved using nanosecond lasers.

Observation of Photoelectron Circular Dichroism Using a Nanosecond Laser.

Photoelectron circular dichroism (PECD) is a fascinating phenomenon both from a fundamental science aspect but also due to its emerging role as a highly sensitive analytic tool for chiral recognition in the gas phase. PECD has been studied with single-photon as well as multi-photon ionization. The latter has been investigated in the short pulse limit with femtosecond laser pulses, where ionization can be thought of as an instantaneous process.

A Dogma in Doubt: Hydrolysis of Equatorial Ligands of Pt Complexes under Physiological Conditions.

Due to their high kinetic inertness and consequently reduced side reactions with biomolecules, Pt complexes are considered to define the future of anticancer platinum drugs. The aqueous stability of a series of biscarboxylato Pt complexes was studied under physiologically relevant conditions. Unexpectedly and in contrast to the current chemical understanding, especially oxaliplatin and satraplatin complexes underwent fast hydrolysis in equatorial position (even in cell culture medium and serum).

Photoelectron Circular Dichroism with Two Overlapping Laser Pulses of Carrier Frequencies ω and 2ω Linearly Polarized in Two Mutually Orthogonal Directions.

Using a model methanelike chiral system, we theoretically demonstrate a possibility to access photoelectron circular dichroism (PECD) by a single experiment with two overlapping laser pulses of carrier frequencies ω and 2ω, which are linearly polarized in two mutually orthogonal directions. Depending on the relative phase, the resulting electric field can be tailored to have two different rotational directions in the upper and lower hemispheres along the polarization of the ω pulse. We predict a strong forward-backward asymmetry in the emission of photoelectrons from randomly oriented samples, which has an opposite sign in the upper and lower hemispheres.

Intermediate state dependence of the photoelectron circular dichroism of fenchone observed via femtosecond resonance-enhanced multi-photon ionization.

The intermediate state dependence of photoelectron circular dichroism (PECD) in resonance-enhanced multi-photon ionization of fenchone in the gas phase is experimentally studied. By scanning the excitation wavelength from 359 to 431 nm, we simultaneously excite up to three electronically distinct resonances. In the PECD experiment performed with a broadband femtosecond laser, their respective contributions to the photoelectron spectrum can be resolved.

Enantiomeric Excess Sensitivity to Below One Percent by Using Femtosecond Photoelectron Circular Dichroism.

Photoelectron circular dichroism (PECD) is experimentally investigated with chiral specimens with varying amounts of enantiomeric excess (ee). As a prototype, we measure and analyze the photoelectron angular distribution from randomly oriented fenchone molecules in the gas phase that result from ionization with circularly polarized femtosecond laser pulses. The quantification of these measurements shows a linear dependence with respect to the ee values.

Electron-energy bunching in laser-driven soft recollisions.

We introduce soft recollisions in laser-matter interaction. They are characterized by the electron missing the ion upon recollision in contrast with the well-known head-on collisions responsible for high-harmonic generation or above-threshold ionization. We demonstrate analytically that soft recollisions can cause a bunching of photoelectron energies through which a series of low-energy peaks emerges in the electron yield along the laser polarization axis.