Synthesis and Biological Evaluation of Shishijimicin A-Type Linker-Drugs and Antibody–Drug Conjugates

Abstract

Our previous studies with shishijimicin A resulted in the total synthesis of this scarce marine natural product and a number of its simpler analogues endowed with picomolar potencies against certain cancer cell lines. Herein, we describe the design, synthesis, and biological evaluation of four linker-drugs, anticipating the construction of antibody–drug conjugates (ADCs) as the ultimate goal of this research program. Using a common payload, the assembly of these linker-drugs utilized different linkers and attachment points, providing opportunities to probe the optimal molecular design of the intended ADCs as targeted cancer therapies. In the course of ADC generation and in vitro evaluation, we identified two linker-drugs with a promising in vitro plasma stability profile and excellent targeted cytotoxicity and specificity. Conjugation of shishijimicin A enediyne payloads through their phenolic moiety represents a novel approach to enediyne ADC creation, while the pharmacological profiles of at least two of the generated ADCs compare well with the profiles of the corresponding clinically approved ADC Kadcyla.

Marine natural products

“…695 A native magnetic resonance MS technique was used to identify the ascidian metabolite polycarpine as a covalent binder to a putative uncharacterised protein (Rv1466) from Mycobacterium tuberculosis . 696 The preparation and biological evaluation of antibody–drug conjugates using shishijimicin A as the cytotoxic payload has identified two promising, plasma-stable, hindered disulfide linker variants worthy of further investigation, 697 while the first synthesis of the 1,2,4-thiadiaole alkaloid polyaurine 698 and numerous new and optimised routes for the synthesis of lamellarins and congeners have been reported. 699–702 Comparative analysis of the microbiome and metabolome of the ascidian Ciona intestinalis has identified numerous differences between environments where it is an invasive pest (Prince Edward Island) vs. populations where it is native (Germany).…”

Anthraquinone-fused enediynes: discovery, biosynthesis and development

“…Encouraged by the successful application of CAL as a payload, new ADCs with AFEs and other enediynes as payloads are also under development. 102,103…”

Antibody-Drug Conjugates Containing Payloads from Marine Origin

“…On the other hand, based on the calicheamicin-based ADCs Mylotarg and Besponsa, in which the antibodies are linked through a sterically hindered disulfide structural motif, the shishijimicin analogs 103 and 104 were also chosen as suitable payloads to attach to the corresponding antibodies through linkers that could be connected either to the phenolic as well as to the disulfide domains, respectively ( Figure 13 ). Importantly, the synthesis delineated and extensively optimized for the shishijimicins by Nicolaou et al gave rapid and efficient access to sufficient amounts of the targeted payloads and made possible the preparation and biological evaluations of the corresponding ADCs [ 163 ].…”