Beyond Pseudo-natural Products: Sequential Ugi/Pictet-Spengler Reactions Leading to Steroidal Pyrazinoisoquinolines That Trigger Caspase-Independent Death in HepG2 Cells

Alonso, Fernando,Galilea, Agustín,Ma?ez, Pau Arroyo,Acebedo, Sofía L.,Cabrera, Gabriela M.,Otero, Marcelo,Barquero, Andrea A.,Ramírez, Javier A.

, p. 1945 - 1955 (2021)

In this work, we describe how stereochemically complex polycyclic compounds can be generated by applying a synthetic sequence comprising an intramolecular Ugi reaction followed by a Pictet-Spengler cyclization on steroid-derived scaffolds. The resulting compounds, which combine a fragment derived from a natural product and a scaffold not found in nature. are both structurally distinct and globally similar to natural products at the same time, and interrogate an alternative region of the chemical space. One of the new compounds showed significant antiproliferative activity on HepG2 cells through a caspase-independent cell-death mechanism, an appealing feature when new antitumor compounds are searched.

Thermolysis and photolysis of two steroidal hydroxamic acid methanesulfonates

Edwards, Oliver E.,Grue-Sorensen, Gunnar,Blackwell, Barbara A.

, p. 857 - 872 (1997)

Thermolysis or photolysis of N-methanesulfonyloxy-4-aza-5α-cholestan- 3-one gave derivatives of 4-azacholestan-3-one, 4-aza-A-nor-B-homocholestan- 3-one, 3-aza-A-norcholestane, bis (4-aza-3-oxocholest-5-en-6-yl) methane, and bis(3-aza-A-norcholestan-3-yl) urea. The corresponding 5β-methanesulfonate gave the 5β (coprostane) analogues. Evidence for the mechanism of formation of these products, including a Favorski-like ring contraction and amide oxidation by methanesulfonic acid, is presented. Detailed 1H and 13C assignments are made for many of the products, and ultraviolet absorption for seven steroidal enamides is tabled. Long-range homo- and heteronuclear NMR connectivities were used to confirm the structure of three dimeric compounds and to assign the configuration of the methoxy function of 4-aza-5-methoxy- A-nor-β-homocholestan-3-one to be 5α. Thermolysis or photolysis of N-methanesulfonyloxy-4-aza-5α-cholestan-3-one gave derivatives of 4-azacholestan-3-one, 4-aza-A-nor-B-homocholestan-3-one, 3-aza-A-norcholestane, bis (4-aza-3-oxocholest-5-en-6-yl) methane, and bis(3-aza-A-norcholestan-3-yl) urea. The corresponding 5β-methanesulfonate gave the 5β (coprostane) analogues. Evidence for the mechanism of formation of these products, including a Favorski-like ring contraction and amide oxidation by methanesulfonic acid, is presented. Detailed 1H and 13C assignments are made for many of the products, and ultraviolet absorption for seven steroidal enamides is tabled. Long-range homo- and heteronuclear NMR connectivities were used to confirm the structure of three dimeric compounds and to assign the configuration of the methoxy function of 4-aza-5-methoxy-A-nor-β-homocholestan-3-one to be 5α.

Fujimoto,Pavlos

, p. 4477 (1965)

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Turner

, (1950)

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Synthesis and biological activity of azasteroidal [3,2-c]- and [17,16-c]pyrazoles

Gupta,Pathak,Jindal

, p. 241 - 247 (2007/10/03)

Cholesterol, testosterone acetate and dehydroepiandrosterone acetate were used as starting materials for the preparation of azasteroidal [3,2-c]- and [17,16-c]pyrazole derivatives. In case of the 4-aza androstane series, a mixture of 5α/5β epimers 8 was obtained, which were separated by chemical methods. The compounds 4, 5, 10, 12, 13, 15, 16 and 18-22 were screened for antiinflammatory activity using the carrageenan rat paw oedema model. Oxirane 22 was found to be around ten times more potent than hydrocortisone. Evaluation of compounds 14, 18 and 19 for their antineoplastic activity was also carried out at the National Cancer Institute, Bethesda, MD, USA, using standard procedures.