Total synthesis and biological evaluation of simplified aplyronine analogues as synthetically tractable anticancer agents

Abstract

Analysis of bound structures and SAR studies led to the function-oriented simplification of the aplyronines; a convergent and modular synthetic platform then enabled the total synthesis and biological evaluation of four novel analogues.

Natural Product Based Antibody Drug Conjugates: Clinical Status as of November 9, 2020

“…In their paper in 2018, the total syntheses of aplyronine A ( 57 ) and D ( 58 ) together with a prospective ADC-warhead ( 59 ) were reported . Then last year, they reported further modifications together with activities against HeLa cells, and although apyrologue D ( 60 ) was significantly less active in its simplified form, it still had reasonable nanomolar activity against this cell line . Thus, these synthetic methods would allow the formation of suitable ADCs that may well overcome the toxicity due to adventitious actin inhibition, particularly if they could be coupled to an ADC system that has to be cleaved within the target organelle, thus avoiding any bystander effects from free warhead due to extracellular hydrolysis.…”

Lewis Base–Brønsted Acid–Enzyme Catalysis in Enantioselective Multistep One‐Pot Syntheses

“…[1][2][3] In recent advances it was demonstrated how elegant advantages of the individual catalytic steps can be exploited without the need for extensive purification, long hands-on times or large amounts of solvents.S ometimes combined approaches even turn out to be superior to individual steps by providing higher overall yields or avoiding the direct handling of certain troublesome materials.N aturally,h owever,t hose potentially fruitful endeavors bear challenges in orchestrating as uitable arrangement of reagents,catalysts and conditions to prevent not only undesired side reactions or decomposition of compounds,but also especially the inactivation of catalysts. [4][5][6][7][8][9][10][11][12][13] Thefocus of the present study is on a-methylated ketones 1 [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] and diols 2, [32][33][34][35][36][37][38][39][40] which are used extensively in natural product syntheses.O ver decades,t hey not only proved indispensable for finding and examining new pharmacologically active agents,but also for elucidating the mode of action of established blockbusters ranking among the most important drugs by sale.…”

“…[4][5][6][7][8][9][10][11][12][13] Thefocus of the present study is on a-methylated ketones 1 [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] and diols 2, [32][33][34][35][36][37][38][39][40] which are used extensively in natural product syntheses.O ver decades,t hey not only proved indispensable for finding and examining new pharmacologically active agents,but also for elucidating the mode of action of established blockbusters ranking among the most important drugs by sale. [41,42] Well-established routes towards ketone 1 [16,31,43] and diols 2 [36,37,[44][45][46][47] apply stoichiometric amounts of reagents ...…”

Lewis‐Base‐Brønsted‐Säure‐Enzym‐Katalyse in enantioselektiven mehrstufigen Eintopf‐Synthesen

“…Natürlich sind diese potenziell vielversprechenden Bemühungen mit der Herausforderung verbunden, ein geeignetes Ensemble von Reagenzien, Katalysatoren und Bedingungen zu orchestrieren, um nicht nur unerwünschte Nebenreaktionen oder die Zersetzungen von Produkten, sondern insbesondere auch die Inaktivierung von Katalysatoren zu verhindern. [4][5][6][7][8][9][10][11][12][13] Im Fokus der vorliegenden Arbeit stehen a-methylierte Ketone 1 [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] und Diole 2, [32][33][34][35][36][37][38][39][40] die in Naturstoffsynthesen in großem Umfang eingesetzt werden. Sie erwiesen sich über Jahrzehnte nicht nur als unverzichtbar fürdie Suche nach und Untersuchung von neuen pharmakologisch aktiven Wirkstoffen, sondern auch fürd ie Aufklärung der Wirkungsweise etablierter Blockbuster,d ie zu den umsatzstärksten Medikamenten zählen.…”

“…Sie erwiesen sich über Jahrzehnte nicht nur als unverzichtbar fürdie Suche nach und Untersuchung von neuen pharmakologisch aktiven Wirkstoffen, sondern auch fürd ie Aufklärung der Wirkungsweise etablierter Blockbuster,d ie zu den umsatzstärksten Medikamenten zählen. [41,42] Etablierte Sequenzen zur Synthese des Ketons 1 [16,31,43] und der Diole 2 [36,37,[44][45][46][47] verwenden stçchiometrische Mengen an Reagenzien und enantiomerenreine Ausgangsmaterialien (Schema 1A-C). [48] Die Methoden wurden bis in die jüngste Vergangenheit jahrzehntelang eingesetzt und erwiesen sich als produktiv und geeignet fürdie Naturstoffsynthese.…”