Targeted Synthesis of Complex Spiro[3H‐indole‐3,2′‐pyrrolidin]‐2(1H)‐ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors

Abstract

Mouse double minute 2 (MDM2) is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from initial clinical trials showed that blocking this interaction with a small‐molecule inhibitor can have great value in the treatment of cancer for patients with p53 wild‐type tumors; however, it also revealed dose‐limiting hematological toxicities and drug‐induced resistance as main issues. To overcome the former, an inhibitor with superior potency and pharmacokinetic properties to ultimately achieve full efficacy with less‐frequent dosing schedules is required. Toward this aim, we optimized our recently reported spiro‐oxindole inhibitors by focusing on the crucial interaction with the amino acid side chain of His96 MDM2 . The designed molecules required the targeted synthesis of structurally complex spiro[indole‐3,2′‐pyrrolo[2,3‐ c ]pyrrole]‐2,4′‐diones for which we developed an unprecedented intramolecular azomethine ylide cycloaddition and investigated the results by computational methods. One of the new compounds showed superior cellular potency over previously reported BI‐0252. This finding is a significant step toward an inhibitor suitable to potentially mitigate hematological on‐target adverse effects.

Drugging All RAS Isoforms With One Pocket

“…It is interesting to note that all the subtly different binding modes for compound 18 arise from a rotation of the iso-indolinone with the privileged indole scaffold remain fixed in all structures. Structural rigidification of the bond between the indole and iso-indolinone resulting in natural product-like structures similar to the approach we took with mdm2 [34] should lead to an improvement of both potency and selectivity. It should be noted that all the observed SI/II-pocket interactions, including those with bound water molecules, have not yet been successfully addressed with one molecule.…”

Synthesis of MDM2-p53 Inhibitor BI-0282 via a Dipolar Cycloaddition and Late-Stage Davis–Beirut Reaction

“…We applied a three component [3 + 2] cycloaddition for the synthesis of 2 and reported a novel intramolecular cycloaddition for compounds 3 and 4 (Figure ). , Aiming for further potency and improvement of PK properties, we found that the rigidified fused-indazole motive (Scheme ) had promising properties and optimized this series to obtain 1 .…”

Synthesis, Biological and In Silico Evaluation of Pure Nucleobase-Containing Spiro (Indane-Isoxazolidine) Derivatives as Potential Inhibitors of MDM2–p53 Interaction

“…As explained in the introduction, and demonstrated in many recent works, these type of spiro-derivatives are able to disrupt the interaction between MDM2 and p53, which is the origin of their anti-proliferative action [53,54]. Therefore, we performed computational studies on our substrates 5a – d to focus mainly on their behaviour as disruptors of MDM2–p53 complex and to predict their activity.…”