Design, synthesis, biological activity evaluation and structure-activity relationships of new steroidal aromatase inhibitors. The case of C-ring and 7β substituted steroids. | LitMetric
Univ Coimbra, CIEPQPF, FFUC, Laboratory of Pharmaceutical Chemistry, Azinhaga de Santa Comba, Pólo III - Pólo das Ciências da Saúde, 3000-548 Coimbra, Portugal. Electronic address:
Published: February 2023
AI Article Synopsis
Article Abstract
In this work, new steroidal aromatase inhibitors (AIs) were designed, synthesized, and tested. In one approach, C-ring substituted steroids namely those functionalized at C-11 position with an α or β hydroxyl group or with a carbonyl group as well as C-9/C-11 steroidal olefins and epoxides were studied. It was found that the carbonyl group at C-11 is more beneficial for aromatase inhibition than the hydroxyl group, and that the C-ring epoxides were more potent than the C-ring olefins, leading to the discovery of a very strong AI, compound 7, with an IC of 0.011 μM, better than Exemestane, the steroidal AI in clinical use, which presents an IC of 0.050 μM. In another approach, we explored the biological activity of A-ring C-1/C-2 steroidal olefins and epoxides in relation to aromatase inhibition and compared it with the biological activity of C-ring C-9/C-11 steroidal olefins and epoxides. On the contrary to what was observed for the C-ring olefins and epoxides, the A-ring epoxides were less potent than A-ring olefins. Finally, the effect of 7β-methyl substitution on aromatase inhibition was compared with 7α-methyl substitution, showing that 7β-methyl is better than 7α-methyl substitution. Molecular modelling studies showed that the 7β-methyl on C-7 seems to protrude into the opening to the access channel of aromatase in comparison to the 7α-methyl. This comparison led to find the best steroidal AI (12a) of this work with IC of 0.0058 μM. Compound 12a showed higher aromatase inhibition capacity than two of the three AIs currently in clinical use.
One very unique feature of oxidorhenium(v) complexes is their dual catalytic activity in both reduction of stable oxyanions like perchlorate ClO and nitrate NO as well as epoxidation of olefins. In our ongoing research efforts, we were interested to study how an electron-withdrawing ligand would affect both these catalytic reactions. Hence, we synthesized the novel bidentate dimethyloxazoline-dichlorophenol ligand HL1 and synthesized oxidorhenium(v) complex [ReOCl(L1)] (1).
A practically intriguing catalytic domino methodology has been developed for the synthesis of highly functionalized pyran and ethene-1,1,2-tricarbonitrile derivatives in a single-pot operation. The -dicyano olefins and the corresponding epoxide were taken as the reactive partners in the presence of a hydrogen bond donor (HBD)-catalyzed condition. The reaction was found to be highly efficient in terms of the formation of sequential C-C and O-C bonds along with an exceptional C-C coupling step through a metal-free organocatalytic pathway.
State Key Laboratory of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, Haihe Laboratory of Sustainable Chemical Transformations, College of Chemistry, Nankai University, Tianjin 300071, China.
ConspectusElectrochemistry has been used as a tool to drive chemical reactions for more than two centuries. With the help of an electrode and a power source, chemists are provided with a system whose potential can be precisely dialed in. The theoretically infinite redox range renders electrochemistry capable of oxidizing or reducing some of the most tenacious compounds.
The efficient conversion of long-chain linear α-olefins (LAOs) into industrially useful epoxides is of pivotal importance. Mukaiyama epoxidation based on the use of molecular oxygen as the sole oxidant and aldehyde as the cosubstrate offers a promising route for LAOs epoxidation. However, challenges associated with epoxide forming selectivity and aldehyde coupling efficiency have long impeded the adoption of Mukaiyama epoxidation in large-scale applications.
Epoxidation of olefins catalyzed by manganese(iii) salophen (MnSalop) immobilized on graphene oxide (GO) modified with 3-aminopropyltrimethoxysilane (GO·NH) has been reported. Characterization of the solid catalyst by FTIR, DR UV-Vis, FESEM, XRD, elemental scanning mappings, TGA/DTG, BET measurements, and ICP analysis aided in understanding the catalyst morphology. It confirmed that there was no significant demetallation or chemical change in MnSalop-GO·NH.
