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Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells, and it is the most frequent form of leukemia diagnosed in Western countries. It is characterized by the proliferation and accumulation of neoplastic B lymphocytes in the blood, lymph nodes, bone marrow and spleen. We report the synthesis and antiproliferative effects of a series of novel ethanoanthracene compounds in CLL cell lines. Structural modifications were achieved via the Diels–Alder reaction of 9-(2-nitrovinyl)anthracene and 3-(anthracen-9-yl)-1-arylprop-2-en-1-ones (anthracene chalcones) with dienophiles, including maleic anhydride and N-substituted maleimides, to afford a series of 9-(E)-(2-nitrovinyl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones, 9-(E)-3-oxo-3-phenylprop-1-en-1-yl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones and related compounds. Single-crystal X-ray analysis confirmed the structures of the novel ethanoanthracenes 23f, 23h, 24a, 24g, 25f and 27. The products were evaluated in HG-3 and PGA-1 CLL cell lines (representative of poor and good patient prognosis, respectively). The most potent compounds were identified as 20a, 20f, 23a and 25n with IC50 values in the ranges of 0.17–2.69 µM (HG-3) and 0.35–1.97 µM (PGA-1). The pro-apoptotic effects of the potent compounds 20a, 20f, 23a and 25n were demonstrated in CLL cell lines HG-3 (82–95%) and PGA-1 (87–97%) at 10 µM, with low toxicity (12–16%) observed in healthy-donor peripheral blood mononuclear cells (PBMCs) at concentrations representative of the compounds IC50 values for both the HG-3 and PGA-1 CLL cell lines. The antiproliferative effect of the selected compounds, 20a, 20f, 23a and 25n, was mediated through ROS flux with a marked increase in cell viability upon pretreatment with the antioxidant NAC. 25n also demonstrated sub-micromolar activity in the NCI 60 cancer cell line panel, with a mean GI50 value of 0.245 µM. This ethanoanthracene series of compounds offers potential for the further development of lead structures as novel chemotherapeutics to target CLL. [ABSTRACT FROM AUTHOR]

Trans‐β‐lactam isomers have garnered much attention as anti‐cancer microtubule targeting agents. Currently available synthetic methods are available for the preparation of enantiopure β‐lactams and favour isomeric cis/trans β‐lactam mixtures. Indirect chiral resolution offers the opportunity for isolation of exclusively enantiopure trans‐β‐lactams. In this study, liquid chromatography chiral resolution of β‐lactams derivatized as diastereomer mixtures with a panel of N‐protected amino acids is explored, where N‐(Boc)‐L‐proline served as the optimal chiral derivatising reagent. High‐performance liquid chromatography failed to adequately determine diastereomeric excess (de) of resolved diastereomers. Variable temperature, 1H NMR and 2D EXSY spectroscopic analyses of proline‐derivatised diastereomers were successfully employed to characterise equilibrating rotamers of resolved diastereomers and determine their de. Integration of resolved resonances corresponding to H3 and H4 of the β‐lactam ring served as a quantitative qNMR tool for the calculation of de following resolution. [ABSTRACT FROM AUTHOR]

The Group for the Promotion of Pharmaceutical Chemistry in Academia (GP2A) held their 30th annual conference in August 2022 in Trinity College Dublin, Ireland. There were 9 keynote presentations, 10 early career researcher presentations and 41 poster presentations. [ABSTRACT FROM AUTHOR]

A series of related substituted 1-(3,4,5-tri­meth­oxy­phen­yl)azetidin-2-ones have been characterized: 3-(4-fluoro­phen­yl)-4-(4-meth­oxy­phen­yl)-1-(3,4,5-tri­meth­oxy­phen­yl)azetidin-2-one, C25H24FNO5 (1), 3-(furan-2-yl)-4-(4-meth­oxy­phen­yl)-1-(3,4,5-tri­meth­oxy­phen­yl)azetidin-2-one, C23H23NO6 (2), 4-(4-meth­oxyphen­yl)-3-(naphthalen-1-yl)-1-(3,4,5-tri­meth­oxy­phen­yl)azetidin-2-one, C29H27NO5 (3), 3-(3,4-di­meth­oxy­phen­yl)-4-(4-meth­oxy­phen­yl)-1-(3,4,5-tri­meth­oxy­phen­yl)azetidin-2-one, C27H29NO7 (4) and 4,4-bis­(4-meth­oxy­phen­yl)-3-phenyl-1-(3,4,5-tri­meth­oxy­phen­yl)azetidin-2-one, C32H31NO6 (5). All of the compounds are racemic. The lactam and 3,4,5-tri­meth­oxy­phenyl rings are approximately co-planar and the orientation of the lactam and the 4-meth­oxy­phenyl substituent is approximately orthogonal. The chiral centres, although eclipsed by geometry, have torsion angles ranging from −7.27 to 13.08° for the 3 position, and −8.69 to 13.76° for the 4 position of the β-lactam. The structures display intra­molecular C—H...O bonding between the 3,4,5-tri­meth­oxy­phenyl ring and the lactam ketone. Further C—H...O inter­actions are observed and form either an opposing meth­oxy `buckle' to join two mol­ecules together or a cyclic dimer. [ABSTRACT FROM AUTHOR]

Nuclear receptors such as the estrogen receptors (ERα and ERβ) modulate the effects of the estrogen hormones and are important targets for design of innovative chemotherapeutic agents for diseases such as breast cancer and osteoporosis. Conjugate and bifunctional compounds which incorporate an ER ligand offer a useful method of delivering cytotoxic drugs to tissue sites such as breast cancers which express ERs. A series of novel conjugate molecules incorporating both the ER ligands endoxifen and cyclofenil-endoxifen hybrids covalently linked to the antimitotic and tubulin targeting agent combretastatin A-4 were synthesised and evaluated as ER ligands. A number of these compounds demonstrated pro-apoptotic effects, with potent antiproliferative activity in ER-positive MCF-7 breast cancer cell lines and low cytotoxicity. These conjugates displayed binding affinity towards ERα and ERβ isoforms at nanomolar concentrations e.g., the cyclofenil-amide compound 13e is a promising lead compound of a clinically relevant ER conjugate with IC50 in MCF-7 cells of 187 nM, and binding affinity to ERα (IC50 = 19 nM) and ERβ (IC50 = 229 nM) while the endoxifen conjugate 16b demonstrates antiproliferative activity in MCF-7 cells (IC50 = 5.7 nM) and binding affinity to ERα (IC50 = 15 nM) and ERβ (IC50 = 115 nM). The ER binding effects are rationalised in a molecular modelling study in which the disruption of the ER helix-12 in the presence of compounds 11e, 13e and 16b is presented These conjugate compounds have potential application for further development as antineoplastic agents in the treatment of ER positive breast cancers [ABSTRACT FROM AUTHOR]