Promising test results on the biological activity of our previously described naphtho[1,2‐d]oxazoles and heterobenz[1,2‐d]oxazoles, obtained by the photochemical cyclization of 5‐phenylethenyl‐ and 5‐heteroarylethenyloxazoles, prompted us to continue with the photochemical synthesis of substituted naphtho[1,2‐d]oxazoles, and to extend the photochemical cyclization to the synthesis of naphtho/heterobenz[2,1‐d]oxazoles from 4‐(aryl/heteroarylethenyl)oxazoles. The required p‐ and o‐phenyl‐substituted 5‐arylethenyloxazoles were prepared from the corresponding α,β‐unsaturated aldehydes and the TosMIC reagent (tosylmethyl isocyanide) by the Van Leusen reaction. The substituted 4‐(aryl/heteroarylethenyl)oxazoles were prepared by the Wittig reaction starting from various phosphonium salts and 2‐H/methyl‐4‐oxazolecarbaldehydes.

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Acetylcholine-induced vasorelaxation (AChIR) and responses to reduced pO2 (hypoxia-induced relaxation (HIR), 0% O2) were assessed in vitro in aortic rings of healthy male Sprague-Dawley rats (N = 252) under hyperbaric (HBO2) protocols. The studied groups consisted of the CTRL group (untreated); the A-HBO2 group (single HBO2; 120 min of 100% O2 at 2.0 bars); the 24H-HBO2 group (examined 24 h after single exposure) and the 4D-HBO2 group (four consecutive days of single HBO2). AChIR, sensitivity to ACh and iNOS expression were decreased in the A-HBO2 group. HIR was prostanoid- and epoxyeicosatrienoic acid (EET)-mediated. HIF-1α expression was increased in the 24H-HBO2 and 4D-HBO2 groups. LW6 (HIF-1α inhibitor) decreased HIR in the 24H-HBO2 group. HBO2 affected the expression of COX-1 and COX-2. CYP2c11 expression was elevated in the 24H-HBO2 and 4D-HBO2 groups. Concentrations of arachidonic acid (AA) metabolites 14(15)-DiHET, 11(12)-DiHET and 8(9)-DiHET were increased in A-HBO2 and 24H-HBO2. An increased concentration of 8(9)-EET was observed in the A-HBO2 and 24h-HBO2 groups vs. the CTRL and 4D-HBO2 groups, and an increased concentration of 5(6)-DiHET was observed in the 24H-HBO2 group vs. the 4D-HBO2 group. The 20-HETE concentration was increased in the A-HBO2 group. All were determined by LC-MS/MS of the aorta. The results show that AChIR in all groups is mostly NO-dependent. HIR is undoubtedly mediated by the CYP450 enzymes’ metabolites of AA, whereas HIF-1α contributes to restored HIR. Vasoconstrictor metabolites of CYP450 enzymes contribute to attenuated AChIR and HIR in A-HBO2.

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One of the main reasons for the high drug attrition rate in oncology is the poor clinical predictive power of 2D cancer cell lines cultures in vitro which are the standard assay used as screening assay to select new chemical entities (NKE) with potent anticancer activity. Therefore, there is increasing interest in developing 3D in vitro cell culture systems, as a primary screening assays which would represent a biologically more relevant assay system, due to similarity to physiological conditions in which tumors growth in living organism. Very important is to develop reproducible 3D cell line culture in vitro assays, feasible for the primary screening of NKEs platforms. Within this manuscript we have tested small platform of selected benzo [b]thieno, thieno [2,3-b]thiophene, and thieno[3,2-b]thiophene 2-carboxanilides, as well as their cyclic derivatives [2,3-c]quinolones, which already showed anti-proliferative activity on other cancer cell lines in 2D system. Platform was tested in 2D and 3D cancer cell culture assays on three human breast cancer cell lines (SK-BR-3, MDA-MB-231, T-47D). Those cell lines were selected on the basis of ability to growth and form cell spheres and also on different sensitivity to chemotherapeutic agents. We used doxorubicin as control compound due similar mode of action, (specific intercalation with the DNA double helix), as tested compound probably have.Obtained results in some cases showed significant disagreement, indicating that in early screening selection of active compounds only on 2D activity basis we could pick up false positive compounds (active only on 2D cell culture lines and not on 3D cell lines for which it is clamed that are more similar to real physiological conditions for tumor growth). One possibility for obtained discrepancy of results obtained on 2D and 3D cell cultures could be physico-chemical properties of compounds. Therefore, we analyzed some physico-chemical properties of active compounds as chrom logD values and calculated structural parameters: number of hydrogen bond donors and acceptors, calculated logP and logD values, molecular weight, ionization constants (pKa), number of aromatic rings, number of rotatable bonds and polar surface area. Association of physico-chemical descriptors with observed anti-proliferative activity has been investigated. Basicity, molecular weight and number of H-bond donors are found to be main factors contributing to the anti-proliferative effect of investigated compounds for both 2D and 3D cell cultures.