Stereoselective Synthesis of Chiral C2-Symmetric 1,3- and 1,5-Bis-Sulfoxides Guided by the Horeau Principle: Understanding the Influence of the Carbon Chain Nature in Its Ability for Metal Coordination.

The stereoselective synthesis of two distinct types of C2-symmetric chiral bis-sulfoxides, 1,3- and 1,5-bis(sulfinyl) derivatives, has been achieved based on the DAG methodology. The 1,5-bis(sulfinyl) derivatives constitute a new family of tridentate chiral ligands thanks to the presence of an additional sulfenyl or sulfinyl group in the carbon chain acting as a bridge. A systematic development and optimization of two synthetic routes, one for each ligand family, have been undertaken, highlighting the strategic utilization of Horeau's law to enhance enantioselectivity. Additionally, palladium (Pd) and ruthenium (Ru) complexes derived from the synthesized bis-sulfoxides were prepared, and their structures were elucidated through spectroscopic analysis. Isolation of Pd(II) complexes involving 1,3-bis-sulfoxides was exclusively achieved using trifluoroacetates as coligands. In the case of Ru(II) complexes, the trans geometry could be determined for 1,3-bis-sulfoxides. The introduction of a third sulfur atom as a coordinating element in the 1,5-bis(sulfinyl) derivatives facilitates the formation of two distinct tricoordinated Ru(II) complexes. The structure of these complexes is intricately influenced by the oxidation state adopted by the central sulfur on the chain, whether as a thioether or as a sulfoxide.

Synthesis and in vitro cytotoxicity of benzoxazole-based PPARα/γ antagonists in colorectal cancer cell lines.

A series of benzoxazole-based amides and sulfonamides were synthesized and evaluated for their human peroxisome proliferator-activated receptor (PPAR)α and PPARγ activity. All tested compounds showed a dual antagonist profile on both PPAR subtypes; based on transactivation results, seven compounds were selected to test their in vitro antiproliferative activity in a panel of eight cancer cell lines with different expression rates of PPARα and PPARγ. 3f was identified as the most cytotoxic compound, with higher potency in the colorectal cancer cell lines HT-29 and HCT116. Compound 3f induced a concentration-dependent activation of caspases and cell-cycle arrest in both colorectal cancer models. Docking experiments were also performed to shed light on the putative binding mode of this novel class of dual PPARα/γ antagonists.

Synthesis and characterization of enantiopure chiral NH2/SO palladium complexes.

A series of enantiopure chiral NH2/SO palladium complexes have been synthesised with high yields by treating the corresponding tert-butylsulfinamide/sulfoxide derivatives with Pd(CH3CN)2Cl2. The enantiopure chiral ligands were prepared by stereoselective addition of tert-butyl or phenyl methylsulfinyl carbanions to different tert-butylsulfinylimines. In all cases, coordination occurs with concomitant desulfinylation. X-ray studies of the Pd complexes showed a higher trans influence of the phenylsulfinyl group in comparison to that of the tert-butylsulfinyl group. Furthermore, we have obtained and characterised two possible palladium amine/sulfonyl complexes, epimers at sulfur, resulting from N-desulfinylation and coordination of palladium with both oxygens of the prochiral sulfonyl group. The catalytic activity and enantioselectivity of the new Pd(II) complexes of acetylated amine/tert-butyl- and phenylsulfoxides in the carboxylated cyclopropanes arylation reaction has been studied, obtaining the best results with the phenylsulfoxide ligand 25(SC,SS) that produced the final arylated product in a 93 :7 enantiomeric ratio.

Biological evaluation of carbohydrate-based aprepitant analogs for neuroblastoma treatment.

Different studies using Aprepitant, a NK1R antagonist currently used as a clinical drug for treating chemotherapy-related nausea and vomiting, have demonstrated that pharmacological inhibition of NK1R effectively reduces the growth of several tumor types such as neuroblastoma (NB). In a previous work, we demonstrated that a series of carbohydrate-based Aprepitant analogs, derived from either d-galactose or l-arabinose, have shown high affinity and NK1R antagonistic activity with a broad-spectrum anticancer activity and an important selectivity. In this new study, we explore the selective cytotoxic effects of these derivatives for the treatment of NB. Furthermore, we describe the design and stereoselective synthesis of a new generation of d-glucose derivatives as Aprepitant analogs, supported by docking studies. This approach showed that most of our carbohydrate-based analogs are significantly more selective than Aprepitant. The galactosyl derivative 2α, has demonstrated a marked in vitro selective cytotoxic activity against NB, with IC50 values in the same range as those of Aprepitant and its prodrug Fosaprepitant. Interestingly, the derivative 2α has shown similar apoptotic effect to that of Aprepitant. Moreover, we can select the glucosyl amino derivative 10α as an interesting hit exhibiting higher in vitro cytotoxic activity against NB than Aprepitant, being 1.2 times more selective.

Unusual report of non-syndromic permanent unilateral mandibular canine agenesis.

Nonsyndromic unilateral permanent canine agenesis, particularly in the lower jaw, is an infrequent clinical observation that has occasionally been reported in the scientific literature. The main aim of the present case report and study is to give insights into the clinical features and genetic information of a nonsyndromic patient affected by unilateral lower canine agenesis and her relatives. A young girl of 9-year-old with a Class II skeletal malocclusion, sella turcica bridging, and severe overjet but no other dental anomalies is described. No associations were found with other types of dental agenesis and previously described genetic variations of the CTNNB1 gene. The possibility of a novel genetic locus should be considered as a possible genetic etiology for this extremely rare condition in a nonsyndromic patient. Based on scientific literature written in English, the present clinical case is one of the first reports to describe a nonsyndromic permanent unilateral mandibular canine agenesis.