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It is well known that combretastatin A4 (CA-4), which is a natural stilbene isolated from Combretum caffrum, is used to inhibit angiogenesis. However, depending on the dose administered to the patient, it can cause some side-effects. Herein, we present the synthesis and structural characterization of a novel N-acylhydrazone derivative – LASSBio-1735 – a CA-4 analogue. LASSBio-1735 has displayed in vitro antiproliferative activity against HL-60 (human leukemia), SF-295 (human glioblastoma), MDA-MB435 (melanoma) and HCT-8 (ileocecal adenocarcinoma) tumor cells. We found different hydration levels in two batches of the as-synthesized compound. As a consequence, we could successfully determine the crystal structures – by using X-ray powder diffraction data and a simulated annealing procedure – of the anhydrous and hydrated forms. The effects on cell viability of anhydrous and hydrated forms of LASSBio-1735 were comparatively evaluated in different tumor cell lines, and the hydrated form exhibited higher cytotoxicity in human leukemia K562 cells. These findings lead us to perform a quantitative phase analysis on one of the samples and may shed some light on the search for possible new solvates and/or hydrates.

Receptor tyrosine kinases (RTKs) are cell-surface proteins that trigger key cellular responses, such as survival, proliferation, differentiation, migration, and cell-cycle control. As increased activity, abundance, and/or cellular distribution of wild-type and mutant forms of RTKs is often associated with tumor establishment, growth, and progression, several drugs directed to clinically relevant RTKs have entered the pharmaceutical market since the beginning of the twenty-first century, representing innovative approaches for cancer treatment. The modulation strategies include small-molecule tyrosine kinase inhibitors (TKIs), targeting the ATP-binding site of the intracellular TK domain, and monoclonal antibodies directed to the extracellular domain, interfering with RTK activation and/or marking RTK-expressing cells for destruction by the immune system. Even though these drugs clearly represented an impressive breakthrough in the therapy of RTK-addicted tumors, resistance development and detection of refractory tumors have given rise to novel therapeutic challenges, pushing the drug discovery process forward. This chapter focuses particularly on the discussion of several case studies on the development of small-molecule tyrosine kinase inhibitors (TKIs) directed to EGFR, VEGFR, and PDGFR, clinically relevant RTKs, and the subset of advances in this field.

Homologation is a concept introduced by Gerhard in 1853 to describe a homologous series in organic chemistry. Since then, the concept has been adapted and used in medicinal chemistry as one of the most important strategies for molecular modification. The homologation types, their influence on physico-chemical properties and molecular conformation are presented and discussed. Its application in lead-identification and lead optimization steps, as well as its impact on pharmacodynamics/pharmacokinetic properties and on protein structure is highlighted from selected examples. • Homologation: definition and types • Homologous series in nature • Comparative physico-chemical and conformational properties • Application in lead-identification and lead-optimization • Impact on pharmacodynamic property • Impact on pharmacokinetic property • Impact on protein structure • Concluding remarks • Acknowledgment • References

Clinical data acquired over the last decade on non-small cell lung cancer (NSCLC) treatment with small molecular weight Epidermal Growth Factor Receptor (EGFR) inhibitors have shown significant influence of EGFR point mutations and in-frame deletions on clinical efficacy. Identification of small molecules capable of inhibiting the clinically relevant EGFR mutant forms is desirable, and novel chemical scaffolds might provide knowledge regarding selectivity among EGFR forms and shed light on new strategies to overcome current clinical limitations. Design, synthesis, docking studies and in vitro evaluation of N-(3-(3-phenylureido)quinoxalin-6-yl) acrylamide derivatives (7a-m) against EGFR mutant forms are described. Compounds 7h and 7l were biochemically active in the nanomolar range against EGFRwt and EGFRL858R. Molecular docking and reaction enthalpy calculations have shown the influence of the combination of reversible and covalent binding modes with EGFR on the inhibitory activity. The inhibitory profile of 7h against a panel of patient-derived tumor cell lines was established, demonstrating selective growth inhibition of EGFR related cells at 10 μM among a panel of 30 cell lines derived from colon, melanoma, breast, bladder, kidney, prostate, pancreas and ovary tumors.

Methodologies to obtain quinoxaline compounds regioselectively are rarely reported in literature, thus regioselective and multi-gram methodologies to obtain these derivatives are desirable to explore the entire potential of these scaffolds for academic and/or commercial application. A facile and multi-gram methodology is described to obtain compound 7-nitroquinoxalin-2-amine using o-phenylenediamine, a cheap and readily available reactant, as starting material in a five-step procedure in good yields and high purity without further purification such as crystallization or column chromatography.

The inherent morbidity and mortality caused by schistosomiasis is a serious public health problem in developing countries. Praziquantel is the only drug in therapeutic use, leading to a permanent risk of parasite resistance. In search for new schistosomicidal drugs, meclonazepam, the 3-methyl-derivative of clonazepam, is still considered an interesting lead-candidate because it has a proven schistosomicidal effect in humans but adverse effects on the central nervous system did not allow its clinical use. Herein, the synthesis, in vitro biological evaluation, and molecular modeling of clonazepam, meclonazepam, and analogues are reported to establish the first structure–activity relationship for schistosomicidal benzodiazepines. Our findings indicate that the amide moiety [N1H-C2(=O)] is the principal pharmacophoric unit of 1,4-benzodiazepine schistosomicidal compounds and that substitution on the amide nitrogen atom (N1 position) is not tolerated.

Cancer is the second most common cause of death in the USA. Among the known classes of anticancer agents, the microtubule-targeted antimitotic drugs are considered to be one of the most important. They are usually classified into microtubule-destabilizing (e.g., Vinca alkaloids) and microtubule-stabilizing (e.g., paclitaxel) agents. Combretastatin A4 (CA- 4), which is a natural stilbene isolated from Combretum caffrum, is a microtubule-destabilizing agent that binds to the colchicine domain on b-tubulin and exhibits a lower toxicity profile than paclitaxel or the Vinca alkaloids. In this paper, we describe the docking study, synthesis, antiproliferative activity and selectivity index of the N-acylhydrazone derivatives (5a– r) designed as CA-4 analogues. The essential structural requirements for molecular recognition by the colchicine binding site of b-tubulin were recognized, and several compounds with moderate to high antiproliferative potency (IC50 values # 18 mM and $4 nM) were identified. Among these active compounds, LASSBio-1586 (5b) emerged as a simple antitumor drug candidate, which is capable of inhibiting microtubule polymerization and possesses a broad in vitro and in vivo antiproliferative profile, as well as a better selectivity index than the prototype CA-4, indicating improved selective cytotoxicity toward cancer cells.

This work describes a novel ligand for peroxisome proliferator-activated receptor gamma (PPARgamma) and its hypoglycemic and analgesic activity in a murine model of diabetes-induced neuropathic pain. The molecular recognition of LASSBio-1772 by a PPARgamma binding domain showed that the compound is a partial agonist. Four weeks after male Wistar rats received a single intravenous injection of streptozotocin (STZ, 60 mg/kg), plasma glucose levels were increased from 92.5 ± 3.7 to 465.0 ± 21.6 mg/dL (P < 0.01) and serum insulin was reduced from 66.8 ± 7.8 to 25.5 ± 5.6 pmol/L (P