Total Synthesis of Shishijimicin A

Abstract

The total synthesis of the rare but extremely potent antitumor agent shishijimicin A has been achieved via a convergent strategy involving carboline disaccharide 3 and hydroxy enediyne thioacetate 4.

Die Bedeutung der organischen Synthese bei der Entstehung und Entwicklung von Antikörper‐Wirkstoff‐Konjugaten als gezielte Krebstherapien

“…Shishijimicin A ( 237 , Schema ) wurde im Jahr 2003 aus der Ascidiae (Seescheide) Didemnum proliferum , die vor der Küste der Fidschi‐Inseln gesammelt wurde, isoliert und zeigte phänomenale Eigenschaften gegen bestimmte Krebszelllinien und erregte so unsere Aufmerksamkeit als potenzieller Wirkstoff oder Leitverbindung für Antikörper‐Wirkstoff‐Konjugate. Die erste Totalsynthese wurde 2015 in unseren Laboratorien erreicht und anschließend 2018 optimiert . Die retrosynthetischen Schnitte (Tafel A), auf deren Grundlage unsere synthetische Strategie entwickelt wurde (Tafel B), und zwei extrem potente Shishijimicin‐A‐Analoga (Tafel C) sind in Schema dargestellt.…”

The Emergence and Evolution of Organic Synthesis and Why It is Important to Sustain It as an Advancing Art and Science for Its Own Sake

“…Figure shows the molecular structures of calicheamicin , shishijimicin A, uncialamycin, N 14 ‐desacetoxytubulysin H, trioxacarcin C, thailanstatin A, epothilone B, namenamicin, and disorazole A 1 , all rare natural or designed molecules that served as inspirations and leads for our research programs in the area of antibody–drug conjugates (ADCs). We found this type of translational research to be immensely satisfying and rewarding in that it preserves our interest in the advancement of our science.…”

The Evolution and Impact of Total Synthesis on Chemistry, Biology and Medicine

“…Shishijimicin A ( 48 , Figure ) is the most cytotoxic of the enediyne antitumor antibiotics with potencies down to subpicomolar IC 50 values to be isolated and synthesized . Its molecular structure is reminiscent to that of calicheamicin , one of the first members of the enediyne class and the first cytotoxic agent to be used as a payload to a clinically approved antibody drug conjugate (ADC, Mylotarg®).…”

“…The scarcity of shishijimicin A coupled with its desirability as a highly valued payload for ADCs prompted us to initiate a program directed toward its total synthesis and to search for simpler and more potent variations of it. Our first approach to this molecule, which included streamlining our original synthesis of the endiyne domain common to shishijimicin A and calicheamicin , was accomplished in 2015 (see summary in Figure , starting from building blocks D – G and through intermediates 66 – 69 ). Our continuing efforts in this area include improving this process even further and applying it to the construction of designed analogues of shishijimicin A for biological evaluation and conjugation to appropriate cancer‐associated antibodies to produce ADCs as potential new cancer therapies.…”

“…Shishijimicin A (48, Figure 1) is the most cytotoxic of the enediyne antitumor antibiotics with potencies down to subpicomolar IC 50 values to be isolated [51] and synthesized. [52] Its molecular structure is reminiscent to that of calicheamicin g I 1 , one of the first members of the enediyne class and the first cytotoxic agent to be used as a payload to a clinically approved antibody drug conjugate (ADC, Mylotarg ® ). Specifically, the two molecules have the same enediyne structural motif but differ substantially in their remaining domains, with shishijimicin A featuring a distinguishing carboline ring system.…”