Diastereomeric Spirooxindoles as Highly Potent and Efficacious MDM2 Inhibitors

Zhao, Yujun; Liu, Liu; Sun, Wei; Lu, Jianfeng; McEachern, Donna; Li, Xiaoqin; Yu, Shanghai; Bernard, Denzil; Ochsenbein, Philippe; Ferey, Vincent; Carry, Jean‐Christophe; Deschamps, Jeffrey R.; Sun, Duxin; Wang, Shaomeng

doi:10.1021/ja3125417

Cited by 217 publications

(143 citation statements)

References 24 publications

Supporting

Mentioning

139

Contrasting

Unclassified

Order By: Relevance

“…14 The architecture of spiroindolinone-3,3′-pyrrolidine series (as exemplified by MI-219) was first reported by Ding et al 16−18 Consistent with our findings, this group recently published their latest findings in which the original stereochemistry was found to be unstable and converted over time to the more stable "Trans" configuration as shown in RO8994. 19 Second, a methoxy para-benzoic acid moiety in RG7388 ("C" in Figure 1) was transferred to RO8994, in which a slight modification was made by converting the terminal carboxylic acid to a carboxamide moiety. In contrast to aliphatic groups, 19,20 the aromatic group ("C") proved to be critical for both RG7388 and RO8994 as it stabilized the molecule metabolically, significantly improved cellular potency/selectivity, PK profiles, and in vivo efficacy.…”

Section: * S Supporting Informationmentioning

confidence: 99%

“…19 Second, a methoxy para-benzoic acid moiety in RG7388 ("C" in Figure 1) was transferred to RO8994, in which a slight modification was made by converting the terminal carboxylic acid to a carboxamide moiety. In contrast to aliphatic groups, 19,20 the aromatic group ("C") proved to be critical for both RG7388 and RO8994 as it stabilized the molecule metabolically, significantly improved cellular potency/selectivity, PK profiles, and in vivo efficacy. 14,15 On the basis of the crystal structures, the 3-chloro-2-fluorophenyl group binds to the Leu26 pocket on MDM2, while the neopentyl group occupies the Phe19 pocket ( Figure 1).…”

Section: * S Supporting Informationmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development

Zhang

Chu

Liu

et al. 2014

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

The development of small-molecule MDM2 inhibitors to restore dysfunctional p53 activities represents a novel approach for cancer treatment. In a previous communication, the efforts leading to the identification of a non-imidazoline MDM2 inhibitor, RG7388, was disclosed and revealed the desirable in vitro and in vivo pharmacological properties that this class of pyrrolidinebased inhibitors possesses. Given this richness and the critical need for a wide variety of chemical structures to ensure success in the clinic, research was expanded to evaluate additional derivatives. Here we report two new potent, selective, and orally active p53-MDM2 antagonists, RO5353 and RO2468, as follow-ups with promising potential for clinical development.KEYWORDS: MDM2, p53, wild-type, small molecule, apoptosis, cancer T umor suppressor p53 is a potent transcription factor that is activated in response to cellular stress and regulates downstream genes controlling cell cycle arrest and apoptosis. 1−4 Dysfunction of the p53 pathway is the most frequent alteration observed in human cancers. 5 MDM2 is the primary negative regulator of p53 through binding to its transactivation domain and promoting proteosomal degradation. 6−8 In tumor cells with wild-type p53 (∼50%), reactivation of the p53 pathway by inhibition of MDM2 with small molecules has been considered as potentially an attractive novel therapeutic approach for cancer treatment. 9,10 Currently, several smallmolecule MDM2 inhibitors including RG7112 and RG7388 (Figure 1) are undergoing clinical evaluations. 11−14 To maximize the chance of success in the clinic and derisk any potential idiopathic toxicity associated with specific chemotypes, continued research efforts are required to expand chemodiversity and identify potent and selective MDM2 antagonists with desirable in vitro ADMET and in vivo pharmacokinetic properties. Here we report the discovery of RO5353 and RO2468, two new highly potent and selective MDM2 inhibitors with potential for clinical development.Our exploration initially led to the identification of a potent and selective MDM2 inhibitor RO8994 (Figure 1), which was found to be highly efficacious against established human tumor xenografts in nude mouse models. 15 Two key structural elements of RG7388 were preserved in RO8994. First, it was established that the stereochemical configuration of the pyrrolidine core structure in which the two aryl rings ("A" and "B") adopt a "Trans" orientation was very important for optimal binding to MDM2. 14 The architecture of spiroindolinone-3,3′-pyrrolidine series (as exemplified by MI-219) was first reported by Ding et al. 16−18 Consistent with our findings, this group recently published their latest findings in which the original stereochemistry was found to be unstable and

show abstract

Section: * S Supporting Informationmentioning

confidence: 99%

Section: * S Supporting Informationmentioning

confidence: 99%

Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development

Zhang

Chu

Liu

et al. 2014

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

show abstract

“…A potential drawback of this compound is a reversible ring-opening-cyclization reaction which generates different diastereomers, starting from a single compound. 32 From a mechanistic point-of-view, this epimerization reaction occurs via a reversible retro-Mannich reaction/cyclization, due to the presence of the nitrogen atom in the pyrrolidine ring. The replacement of the pyrrolidine ring by a cytopentane ring as in D should give access to more robust diastereomers which are less prone to epimerization, while retaining analogous properties overall.…”

Section: Scheme 33 Postulated Reaction Intermediatesmentioning

confidence: 99%

Phosphine Organocatalysis for the Synthesis of Spirocyclic Compounds

Voituriez

Marinetti

Gicquel

2014

Synlett

View full text Add to dashboard Cite

This account describes the use of phosphines as simple organocatalysts that catalyze the synthesis of complex spirocyclic compounds. Besides our own results, coverage of relevant literature in this field is also provided, including asymmetric variants and synthetic applications. Cycloaddition Reactions Using Ynone Derivatives 5 Cycloaddition Reactions Involving Methyl Vinyl Ketone Derivatives 6 Miscellaneous Reactions 7 Conclusions

show abstract

“…[2] Notably, a valuable collection of fully synthetic spirooxindoles are disclosed as drug candidates and leading compounds, for example, MI-888 (E) acted as an efficacious MDM2 Inhibitor. [3] Generally, these spirooxindole moieties are synthesized via nucleophilic addition and spirocyclization on isatin or 3-alkylidine oxindole. [4,5] From the synthetic viewpoint, difunctionalization of alkenes represents an efficient tool for the synthesis of complex compound, and palladium has been proven to be one of the best catalysts in the last decades.…”

Section: Introductionmentioning

confidence: 99%