Eirik Johansson Solum

Synthesis, cytotoxic effects and tubulin polymerization inhibition of 1,4-disubstituted 1,2,3-triazole analogs of 2-methoxyestradiol

Thirteen 1,4-disubstituted 1,2,3-triazole analogs of 2-methoxyestradiol were prepared and tested for their cytotoxic and tubulin polymerization inhibition effects. Two compounds, 11j and 11k, exhibited anti-proliferative effects at low micromolar concentrations. The two analogs 11j and 11k also inhibited tubulin assembly with IC50 values of 8.1 and 5.9μM, respectively.

Synthesis and Pharmacological Effects of the Anti-Cancer Agent 2-Methoxyestradiol

The endogenous steroid 2-methoxyestradiol (2-ME) is a metabolite of 17β-estradiol and its biosynthesis is well established. Moreover, 2-ME is also biosynthesized from estrone. For several years, 2-ME was perceived as an inactive metabolite devoid of any interesting biological activities. Since the late 1980s, a number of biological and pharmacological studies have revealed that 2-ME possesses interesting anti-cancer effects without any undesirable estrogen activity. In particular, the anti-vascular effects and anti-angiogenic activities that 2-ME exhibit, are of great interest and importance, in view of the development of new anti-cancer drugs based on 2-ME. Several clinical trial development programs have been initiated using the steroid 2-ME. In addition, based on the many pharmacological activities reported for 2-ME, but also due to the general interest in total and semi-synthesis of endogenous steroids, several research groups working with organic synthesis have prepared this steroid. Herein, the anti-cancer effects, the results from the clinical trial development programs and the synthetic studies towards 2-ME, are reviewed.

Regioselective monoalkylation of 17β-estradiol for the synthesis of cytotoxic estrogens

Graphical abstract Figure. No caption available. HighlightsRegioselective synthesis of estrogens achieved.A convenient one‐pot protocol was used that tolerates air and moist.Analogs of the steroid metabolite 2‐methoxyestradiol were prepared as potential new anti‐cancer agents.Some analogs showed anti‐proliferative effects in the low micromolar range observed in the CEM and HeLa cell lines. ABSTRACT The regioselective synthesis of estrogens and their derivatives continues to be of interest. Most reported syntheses require multistep protocols associated with poor overall yield and lack of regioselectivity. New preparative protocols are still desired. Herein, 11 2‐alkylated 17&bgr;‐estradiol analogs were synthesized in a highly regioselective manner. The products were obtained using a convenient, one pot and high‐yielding protocol. The anti‐proliferative activity of the compounds was tested in human T‐cell leukemia (CEM), human cervix carcinoma (HeLa) and human dermal microvascular endothelial (HMEC‐1) cells.

Synthesis, biological evaluation and molecular modeling of new analogs of the anti-cancer agent 2-methoxyestradiol: potent inhibitors of angiogenesis

The synthesis, cytotoxicity, inhibition of tubulin polymerization and anti-angiogenic effects of 10 analogs of 2-methoxyestradiol are reported. These efforts revealed that the analog with a 4-pyridine ring in the 17-position, in combination with 2-ethyl- and 3-sulfamate substituents on the steroid A-ring, is the most interesting anti-cancer agent. This compound showed potent inhibitory effects against angiogenesis (IC50 = 0.1 ± 0.02 μM) and selective cytotoxic effects towards the CEM, H460 and HT-29 cancer cell lines, with no cytotoxicity observed against the healthy VERO cell line. The most interesting analog also displayed inhibition of tubulin polymerization (IC50 = 4.3 μM) almost as potent as 2-methoxyestradiol (IC50 = 3.5 μM). Molecular modeling experiments showed that this analog interacts within the colchicine-binding site of β-tubulin via multiple bonding with several amino acids. These observations provide support that the cytotoxic and anti-angiogenic effects observed for this novel analog are, at least in part, mediated by binding to tubulin.

Synthesis, antibacterial evaluation, and docking studies of azaisoflavone analogues generated by palladium-catalyzed cross coupling

Palladium-catalyzed, cross-coupling reaction of N-methyl-3-iodo-4-quinolone with boronic acids or N-methyliminodiacetic acid boronates to obtain azaisoflavone derivatives was investigated through conventional Suzuki–Miyuara coupling or by slow release strategy. It has been observed that a slow release approach was a highly successful. In addition, a series of novel azaisoflavones containing alkynyl group were synthesized via Sonogashira reaction. The antibacterial activities of the all synthesized compounds were screened against series of bacterial strains. Furthermore, a molecular docking study was carried out for the most active compounds using Leadit 2.1.8 docking software, and the results were in good agreement with the experimental data. The details of synthetic methods, spectroscopic data, and biological results are reported.Graphical abstract

Differential effects of some novel synthetic oestrogen analogs on oxidative PC12 cell death caused by serum deprivation

Abstract Oestrogens with no or reduced oestrogen receptor (ER) binding properties are reported to have neuroprotective functions. However, we have previously shown that the hormonally inactive isomer of 17β-estradiol (17β-E), 17α-estradiol (17α-E), down-regulates glutathione (GSH) synthesis, and fails to rescue serum deprivation-induced cell death in the rat pheochromocytoma cell line PC12 in micromolar concentration. The present study examined cellular protective effects of new 17β-E analogs and 2-methoxyestradiol (2-ME) analogs with no or little oestrogen activity. 17β-E, 17α-E, 2-ME, and an antagonist of the G protein-coupled oestrogen receptor (GPER), G36, were also included. Both 17α-E and 2-ME protected against deprivation-induced cell death in PC12 cells at 1 nM, but they enhanced the deprivation-induced cell death accompanied by caspase 3 activity and decreased intracellular GSH levels during deprivation at 10 µM. In addition, 10 μM 17α-E activated the p38 mitogen activated protein kinase pathway, which was linked to the enhanced death and reduced GSH levels. Analogs of 2-ME modified with a 6-isoquinoline moiety (6iq) protected against deprivation-induced cell death at 1 nM and did not interfere with the GSH levels nor increase p38 protein levels at 10 µM. The promoter activity of the catalytic subunit of the rate-limiting enzyme, glutamate cysteine ligase (GCLC) in GSH synthesis as well as protein levels of GCLC and Nrf2, increased with the 2-ME analogs at 10 µM. In conclusion, the steroids have differential protective effects, and modifying 2-ME may give the steroid more favourable properties than 17α-E, 2-ME, and G36 in regard to GSH regulation.

Practical synthesis of silyl-protected and functionalized propargylamines using nanostructured Ag/TiO2 and Pt/TiO2 as active recyclable catalysts

Herein we report the use of Ag/TiO2 and Pt/TiO2 nanocatalysts to promote the synthesis of a series of silyl-protected and functionalized propargylamine derivatives through alkyne–amine–aldehyde (A3) coupling under microwave condition using water as solvent in short reaction times with high yielding production. A comparative study between the two catalysts was also demonstrated to prove that Pt/TiO2 nanocomposite has higher potential effect for propargylamines synthesis more than Ag/TiO2. The main features of the investigated method for propargylamines synthesis were easy handling, low catalyst loading as well as the feasibility of catalyst recyclability. The prepared compounds are potentially beneficial with possible pharmacological and biological properties, which that could be used in several disciplines including medicinal and agricultural applications.Graphical abstract