Streamlined Total Synthesis of Shishijimicin A and Its Application to the Design, Synthesis, and Biological Evaluation of Analogues thereof and Practical Syntheses of PhthNSSMe and Related Sulfenylating Reagents

Abstract

Shishijimicin A is a scarce marine natural product with highly potent cytotoxicities, making it a potential payload or a lead compound for designed antibody-drug conjugates. Herein, we describe an improved total synthesis of shishijimicin A and the design, synthesis, and biological evaluation of a series of analogues. Equipped with appropriate functionalities for linker attachment, a number of these analogues exhibited extremely potent cytotoxicities for the intended purposes. The synthetic strategies and tactics developed and employed in these studies included improved preparation of previously known and new sulfenylating reagents such as PhthNSSMe and related compounds.

The Role of Organic Synthesis in the Emergence and Development of Antibody–Drug Conjugates as Targeted Cancer Therapies

“…A) Retrosyntheticanalysis;B )total synthesis;and C) designed analoguesand their potencies against aselect number of cell lines ( , 2018. [100] ation as ap otential payload, or lead compound, for further investigations.The first total synthesis of this challenging and scarce natural product was recently accomplished by the Paterson group. [120] Their strategy was inspired by the retrosynthetic disconnections shown in Scheme 15 A.…”

“…Isolated in 2003 from the ascidian Didemnum proliferum , collected off the coast of the Fiji Islands, shishijimicin A ( 237 , Scheme ) exhibited phenomenal properties against certain cancer cell lines, and thus attracted our attention as a potential payload, or lead compound, for antibody–drug conjugates. Its first total synthesis was achieved in our laboratories in 2015 and subsequently improved as reported in 2018 . The retrosynthetic disconnections (panel A) based on which our synthetic strategy was developed (panel B) and two extremely potent shishijimicin A analogues (panel C) are shown in Scheme .…”

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.…”

A Review of Heterolytic Synthesis Methodologies for Organotri- and Organotetrasulfane Synthesis

“…Unfortunately, this produced the required PhthNSSMe transfer reagent in only 19% yield. Recently, Nicolaou improved on synthesis of this reagent in his shishijimicin A synthesis 86 using first reaction of sulfur monochloride (S 2 Cl 2 ) with phthalimide to furnish bis(1phthalimidyl)disulfane, (PhthN) 2 S 2 , which could be efficiently converted into phthalimidosulfenyl chloride, (PhthNSCl), with SO 2 Cl 2 in 98% overall yield for the two steps. The sulfenyl chloride was found to be stable in a desiccator at room temperature for several months, making it a very useful reagent for hetero tri-and tetrasulfane synthesis for the future.…”