Sorafenib is a clinically important oral tyrosine kinase inhibitor for the treatment of various cancers. However, the oral bioavailability of sorafenib tablet (Nexavar) is merely 38–49% relative to the oral solution, due to the low aqueous solubility of sorafenib and its relatively high daily dose. It is desirable to improve the oral bioavailability of sorafenib to expand the therapeutic window, reduce the drug resistance, and enhance patient compliance. In this study, we observed that the solubility of sorafenib could be increased ∼50-fold in the coexistence of poly(vinylpyrrolidone-vinyl acetate) (PVP-VA) and sodium lauryl sulfate (SLS), due to the formation of PVP-VA/SLS complexes at a lower critical aggregation concentration. The enhanced solubility provided a faster initial sorafenib dissolution rate, analogous to a forceful “spring” to release drug into solution, from tablets containing both PVP-VA and SLS. However, SLS appears to impair the ability of PVP-VA to act as an efficient “parachute” to ke...

Improving Oral Bioavailability of Sorafenib by Optimizing the “Spring” and “Parachute” Based on Molecular Interaction Mechanisms

Characteristics of known drug space. Natural products, their derivatives and synthetic drugs

Six morpholine-(iso)thiosemicarbazone hybrids HL1–HL6 and their Cu(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu(II) complexes [Cu(L1–6)Cl] (1–6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2–5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC50 values at 2–5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands l...

New Water-Soluble Copper(II) Complexes with Morpholine–Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action

Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety.

The natural product celastrol (1) possesses numerous beneficial therapeutic properties and affects numerous cellular pathways. The mechanism of action and cellular target(s) of celastrol, however, remain unresolved. While a number of studies have proposed that the activity of celastrol is mediated through reaction with cysteine residues, these observations have been based on studies with specific proteins or by in vitro analysis of a small fraction of the proteome. In this study, we have investigated the spatial and structural requirements of celastrol for the design of suitable affinity probes to identify cellular binding partners of celastrol. Although celastrol has several potential sites for modification, some of these were not synthetically amenable or yielded unstable analogues. Conversion of the carboxylic acid functionality to amides and long-chain analogues, however, yielded bioactive compounds that induced the heat shock response (HSR) and antioxidant response and inhibited Hsp90 activity. This led to the synthesis of biotinylated celastrols (23 and 24) that were used as affinity reagents in extracts of human Panc-1 cells to identify Annexin II, eEF1A, and β-tubulin as potential targets of celastrol.

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Celastrol analogues as inducers of the heat shock response. Design and synthesis of affinity probes for the identification of protein targets.

The theoretical prediction power of the software package QikProp was tested. This was achieved by comparing experimentally known results to predicted values. First, simple molecular descriptors for physicochemical properties: octanol-water partition (log P), water solubility (log S), dipole moment, Ionisation Potential (IP) and Electron Affinity (EA) were compared to their experimentally determined counterparts. For all of the descriptors, except EA, a relatively good linear correlation was obtained. Experimentally derived EA values are relatively scarce and often quite inconsistent, which made it difficult to construct a reliable test collection. When compared to values calculated by the Density Functional Theory (DFT) method a reasonable correlation was observed but there is much room for improvement. A clear Gaussian distribution pattern was obtained when a collection of similar to 470 marketed orally bioavailable drug compounds was used to generate the physicochemical properties investigated. The idea was explored whether the prediction power of ADME modules could be tested in a qualitative way, based on broad assumptions, using different classes of marketed drug compounds. It was found that this approach gives one a good idea about which modules deserve further attention for evaluation. In this way it is concluded that cell permeation and the blood - brain barrier modules merit more evaluation work whereas work on the HERG K+ and CNS activity modules was discontinued.

Saira Naeem

Papers

Benchmarking the reliability of QikProp. Correlation between experimental and predicted values