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Despite the increasing incidence of hepatocellular carcinoma (HCC) worldwide, current pharmacological treatments are still unsatisfactory. We have previously shown that lysophosphatidic acid receptor 6 (LPAR6) supports HCC growth and that 9-xanthenylacetic acid (XAA) acts as an LPAR6 antagonist inhibiting HCC growth without toxicity. Here, we synthesized four novel XAA derivatives, (±)-2-(9H-xanthen-9-yl)propanoic acid (compound 4 - MC9), (±)-2-(9H-xanthen-9-yl)butanoic acid (compound 5 - MC6), (±)-2-(9H-xanthen-9-yl)hexanoic acid (compound 7 - MC11), and (±)-2-(9H-xanthen-9-yl)octanoic acid (compound 8 - MC12, sodium salt) by introducing alkyl groups of increasing length at the acetic α-carbon atom. Two of these compounds were characterized by X-ray powder diffraction and quantum mechanical calculations, while molecular docking simulations suggested their enantioselectivity for LPAR6. Biological data showed anti-HCC activity for all XAA derivatives, with the maximum effect observed for MC11. Our findings support the view that increasing the length of the alkyl group improves the inhibitory action of XAA and that enantioselectivity can be exploited for designing novel and more effective XAA-based LPAR6 antagonists.

The reactivity of 2-(prop-2-ynylthio)-1 H-benzo[d]imidazoles and their corresponding hydrobromide salts under PdI2/KI-catalyzed oxidative aminocarbonylation conditions has been studied. It is found that 2-prop-2-ynylsulfanyl-3 H-benzimidazolium salts, when allowed to react with amines, carbon monoxide, and oxygen, under the catalytic action of PdI2 (1 mol %) in conjunction with KI (1 equiv), under suitable conditions (80 °C and 20 atm of a 4:1 mixture of CO/air, in MeCN, and in the presence of a six-fold excess of amine, for 15 h), could be selectively converted into 2-benzo[4,5]imidazo[2,1-b]thiazol-3-yl-N,N-dialkylacetamides in 60–78 % yields, through an oxidative aminocarbonylation/heterocyclization process. The structure of a representative product, 2-benzo[4,5]imidazo[2,1-b]thiazol-3-yl-1-pyrrolidin-1-ylethanone, was confirmed by X-ray diffraction analysis.

Innovative methodologies, introduced in the software EXPO and working both in the reciprocal and in the direct space, can be successfully adopted for solving crystal structure by X-ray powder diffraction data. The principles underlying these methodologies are summarized. Three representative examples of crystal structure solution of the peptides Z-(Aib)2-OH, Z-(Aib)3-O-t-Bu and Z-(Aib)4-OH are discussed in relation to their different degree of structure complexity.

The reactivity of 2-(prop-2-ynylthio)-1 H-benzo[d]imidazoles and their corresponding hydrobromide salts under PdI2/KI-catalyzed oxidative aminocarbonylation conditions has been studied. It is found that 2-prop-2-ynylsulfanyl-3 H-benzimidazolium salts, when allowed to react with amines, carbon monoxide, and oxygen, under the catalytic action of PdI2 (1 mol %) in conjunction with KI (1 equiv), under suitable conditions (80 °C and 20 atm of a 4:1 mixture of CO/air, in MeCN, and in the presence of a six-fold excess of amine, for 15 h), could be selectively converted into 2-benzo[4,5]imidazo[2,1-b]thiazol-3-yl-N,N-dialkylacetamides in 60–78 % yields, through an oxidative aminocarbonylation/heterocyclization process. The structure of a representative product, 2-benzo[4,5]imidazo[2,1-b]thiazol-3-yl-1-pyrrolidin-1-ylethanone, was confirmed by X-ray diffraction analysis.

This work demonstrates how the directing ability of the azetidine ring could be useful for regioselective ortho-CH functionalization of aryl compounds. Robust polar organometallic (lithiated) intermediates are involved in this synthetic strategy. The reagent n-hexyllithium emerged as a safer, yet still effective, basic reagent for the hydrogen/lithium permutation relative to the widely used reagent nBuLi. Two different reaction protocols were discovered for regioselective lithiation at the ortho positions adjacent to the azetidine ring, which served as a toolbox when other competing directing groups were installed on the aromatic ring. The coordinating ability of the azetidine nitrogen atom, as well as the involvement of dynamic phenomena related to the preferential conformations of 2-arylazetidine derivatives, were recognized to be responsible for the observed reactivity and regioselectivity. A site-selective functionalization of the aromatic ring was achieved for aryl azetidines with either coordinatively competent groups (e.g. methoxy) or inductively electron-withdrawing substituents (e.g. chlorine and fluorine). By fine-tuning the reaction conditions, regioselective introduction of several substituents on the aromatic ring could be realized. Several substitution patterns were accomplished, which included 1,2,3-trisubstitution, 1,2,3,4-tetrasubstitution, and 1,2,3,4,5-pentasubstitution, up to the exhaustive substitution of the aromatic ring.