Synthesis, molecular editing, and biological assessment of the potent cytotoxin leiodermatolide.

It was by way of total synthesis that the issues concerning the stereostructure of leiodermatolide (1) have recently been solved; with the target now being unambiguously defined, the mission of synthesis changes as to secure a meaningful supply of this exceedingly scarce natural product derived from a deep-sea sponge. To this end, a scalable route of 19 steps (longest linear sequence) has been developed, which features a catalytic asymmetric propargylation of a highly enolizable ß-keto-lactone, a ring closing alkyne metathesis and a modified Stille coupling as the key transformations. Deliberate digression from this robust blueprint brought a first set of analogues into reach, which allowed the lead qualities of 1 to be assessed. The acquired biodata show that 1 is a potent cytotoxin in human tumor cell proliferation assays, distinguished by GI50 values in the ≤3 nM range even for cell lines expressing the Pgp efflux transporter. Studies with human U2OS cells revealed that 1 causes mitotic arrest, micronucleus induction, centrosome amplification and tubulin disruption, even though no evidence for direct tubulin binding has been found in cell-free assays; moreover, the compound does not seem to act through kinase inhibition. Indirect evidence points at centrosome declustering as a possible mechanism of action, which provides a potentially rewarding outlook in that centrosome declustering agents hold promise of being inherently selective for malignant over healthy human tissue.

Best of both worlds: An expansion of the state of the art pKa model with data from three industrial partners.

In a unique collaboration between Simulations Plus and several industrial partners, we were able to develop a new version 11.0 of the previously published in silico pKa model, S+pKa, with considerably improved prediction accuracy. The model's training set was vastly expanded by large amounts of experimental data obtained from F. Hoffmann-La Roche AG, Genentech Inc., and the Crop Science division of Bayer AG. The previous v7.0 of S+pKa was trained on data from public sources and the Pharmaceutical division of Bayer AG. The model has shown dramatic improvements in predictive accuracy when externally validated on three new contributor compound sets. Less expected was v11.0's improvement in prediction on new compounds developed at Bayer Pharma after v7.0 was released (2013-2023), even without contributing additional data to v11.0. We illustrate chemical space coverage by chemistries encountered in the five domains, public and industrial, outline model construction, and discuss factors contributing to model's success.

Employing PEDOT as the p-Type Charge Collection Layer in Regular Organic-Inorganic Perovskite Solar Cells.

Organic-inorganic halide perovskite solar cells have recently emerged as high-performance photovoltaic devices with low cost, promising for affordable large-scale energy production, with laboratory cells already exceeding 20% power conversion efficiency (PCE). To date, a relatively expensive organic hole-conducting molecule with low conductivity, namely spiro-OMeTAD (2,2',7,7'-tetrakis(N,N-di-p-methoxyphenyl-amine) 9,9'- spirobifluorene), is employed widely to achieve highly efficient perovskite solar cells. Here, we report that by replacing spiro-OMeTAD with much cheaper and highly conductive poly(3,4-ethylenedioxythiophene) (PEDOT) we can achieve PCE of up to 14.5%, with PEDOT cast from a toluene based ink. However, the stabilized power output of the PEDOT-based devices is only 6.6%, in comparison to 9.4% for the spiro-OMeTAD-based cells. We deduce that accelerated recombination is the cause for this lower stabilized power output and postulate that reduced levels of p-doping are required to match the stabilized performance of Spiro-OMeTAD. The entirely of the materials employed in the perovskite solar cell are now available at commodity scale and extremely inexpensive.