Future medicinal chemistry · 2025
Aza-peptide aldehydes and ketones: synthesis and evaluation as human 20S proteasome inhibitors.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Corrigan Thomas S, Border Sarah E, Lotti Diaz Leilani M, Kasper Kayla Q, Noonchester Abigail M, Amer Rasmiah, Kucway Kayla S, Fleisher Michael, Fernandez Joseph P, Lovins Alex R, Serrano Ana K, Caffrey Conor R, O'Donoghue Anthony J, Benson Don M, Hadad Christopher M, Ekici Özlem Doğan
Аннотация
AIMS: Aza-peptide aldehydes and ketones were developed as a new class of peptidyl analogues to inhibit the human constitutive (c)20S proteasome as alternative therapeutics to treat multiple myeloma (MM).
MATERIAL AND METHODS: Eleven new aza-peptide aldehydes and ketones were designed based on their preference to bind at the ß5 catalytic subunit of c20S proteasome with benzyloxycarbonyl(Cbz)-Leu-Leu-Leu (MG132-like) and morpholinyl(Mp)-Homophenylalanyl(HPh)-Leu-Phe-Leu (Carfilzomib-like) sequences, synthesized, structurally characterized and evaluated for their inhibitory potency in competitive kinetic assays in vitro. Additionally, cell viability assays and molecular modeling experiments were designed and performed in support.
RESULTS: Aza-peptide aldehydes and ketones generated inhibitory activity with IC50 values in the µM range when tested at the ß5 catalytic subunit of the human c20S proteasome. Compound 1 was the most potent compound with an IC50 value of 2.3 ± 1.5 µM. When tested for concentration-dependent killing of three multiple myeloma, one leukemic and two normal natural killer (NK) cell lines, two compounds generated mid-µM EC50 values only for the cancer cells after 48 h.
CONCLUSIONS: Overall, aza-peptide aldehydes and ketones are a new class of selective human c20S proteasome inhibitors with the potential for further development as alternative therapeutics for multiple myeloma.
MATERIAL AND METHODS: Eleven new aza-peptide aldehydes and ketones were designed based on their preference to bind at the ß5 catalytic subunit of c20S proteasome with benzyloxycarbonyl(Cbz)-Leu-Leu-Leu (MG132-like) and morpholinyl(Mp)-Homophenylalanyl(HPh)-Leu-Phe-Leu (Carfilzomib-like) sequences, synthesized, structurally characterized and evaluated for their inhibitory potency in competitive kinetic assays in vitro. Additionally, cell viability assays and molecular modeling experiments were designed and performed in support.
RESULTS: Aza-peptide aldehydes and ketones generated inhibitory activity with IC50 values in the µM range when tested at the ß5 catalytic subunit of the human c20S proteasome. Compound 1 was the most potent compound with an IC50 value of 2.3 ± 1.5 µM. When tested for concentration-dependent killing of three multiple myeloma, one leukemic and two normal natural killer (NK) cell lines, two compounds generated mid-µM EC50 values only for the cancer cells after 48 h.
CONCLUSIONS: Overall, aza-peptide aldehydes and ketones are a new class of selective human c20S proteasome inhibitors with the potential for further development as alternative therapeutics for multiple myeloma.