Synthesis and evaluation of Apogossypol atropisomers as potential Bcl-xL antagonists

Wei, Jun; Rega, Michele F.; Kitada, Shinichi; Yuan, Hongbin; Zhai, Dayong; Risbood, Prabhakar A.; Seltzman, Herbert H.; Twine, Charles E.; Reed, John C.; Pellecchia, Maurizio

doi:10.1016/j.canlet.2008.07.031

Cited by 26 publications

(35 citation statements)

References 23 publications

(21 reference statements)

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“…Recently, the same team reported the preparation and isolation of both enantiomers of apogossypol [102]. Whilst binding analyses failed to show preferential activity for either enantiomer both had better affinity for Bcl-x L and Mcl-1 than the racemate (albeit marginally) [118]. Apogossypol has an improved pharmacokinetic profile compared to Gossypol with increased blood concentration due to lower clearance rate [119].…”

Section: Apogossypol and Derivativesmentioning

confidence: 95%

Bcl-2 Family Proteins as Therapeutic Targets

Czabotar¹,

Lessène

2010

CPD

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The mitochondrion provides the stage for the interplay of molecular interactions that regulate apoptosis via the intrinsic pathway. The release of apoptogenic factors from this compartment constitutes a critical juncture in this apoptotic pathway. Regulation of the integrity of the outer mitochondrial membrane (OMM) is the task of the Bcl-2 family of proteins. A network of interactions between the various subgroups of the family decides the apoptotic fate of a cell and, as such, an imbalance within this network can lead to a variety of disease states. In particular, over-expression of pro-survival Bcl-2 family proteins is a hallmark of many cancers. Here we discuss recent advances in targeting the Bcl-2 family with both peptides and small molecules.

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Section: Apogossypol and Derivativesmentioning

confidence: 95%

Bcl-2 Family Proteins as Therapeutic Targets

Czabotar¹,

Lessène

2010

CPD

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“…Given that gossypol and AT-101 have toxicity problems likely due to two reactive aldehyde groups at 8, 8′-positions on the naphthalene rings, a semi-synthetic derivative apogossypol, was synthesized lacking two aldehyde groups, with enhanced activity and reduced toxicity [41, 54, 55]. Apogossypol and gossypol are shown to exhibit similar oral and intravenous pharmacokinetic profiles as well as in vitro stability, although apogossypol demonstrated a slower clearance rate, larger AUC (area under curve), and better microsomal stability [55, 56] suggesting favorable pharmacokinetics for this analogue.…”

Section: Apogossypolmentioning

confidence: 99%

“…Because gossypol enantiomers displayed differential pro-apoptotic activities, atropisomers of apogossypol were synthesized, evaluated and compared with racemic apogossypol for cellular activity [54]. 5, 5′ substituted ketone and amide apogossypol derivatives such as BI-79D10, compound 8r and BI-97C1 (sabutoclax) were synthesized.…”

Section: Apogossypolmentioning

confidence: 99%

Bcl-2 antagonists: a proof of concept for CLL therapy

Balakrishnan

Gandhi

2013

Invest New Drugs

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Defective apoptosis is a fundamental hallmark feature of CLL biology and is a major target of cancer therapy development. High levels of Bcl-2 family anti-apoptotic proteins are considered primarily responsible for inhibiting apoptosis in CLL cells. While several approaches were considered to selectively inhibit Bcl-2 family anti-apoptotic proteins, the discovery that gossypol binds and antagonizes anti-apoptotic effect of Bcl-2 family proteins was a major breakthrough in identifying specific Bcl-2 antagonists. The concept of mimicking BH3 domain emphasized the importance of Bcl-2 family-targeted therapy that can modulate the function of anti-apoptotic proteins. Although parent compound gossypol did not sustain in the clinic, its structural modifications led to the development of additional analogues that demonstrated improved efficacy and reduced toxicity in preclinical and clinical investigations. Proof of concept of this hypothesis was demonstrated by structure based BH3 mimetic ABT-737 that has shown greater cytotoxicity towards CLL cells both in pre-clinical models and clinical trials. Its oral compound ABT-263 has demonstrated the substantial susceptibility of chronic lymphocytic leukemia cells through Bcl-2 inhibition. Collectively, results of a Phase I Study of Navitoclax (ABT-263) in patients with relapsed or refractory disease warrants Bcl-2 as a valid therapeutic target in CLL. Importantly, molecules that mimic pro-apoptotic BH3 domains represent a direct approach to overcoming the protective effects of anti-apoptotic proteins such as Mcl-1, Bcl-2 and Bcl-XL.

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“…As Obatoclax targets Mcl-1, unlike ABT-737, potential synergistic effects with ABT-737 could be exploited and Mcl-1 dependent malignancies could be targeted. Another group of compounds, Gossypol and Apo-Gossypol target the BH3 hydrophobic grove, but other established mechanisms make these compounds less specific, which is also borne out in the reported toxicities of Gossypol [132–134]. …”

Section: Targeting the Bcl-2 Rheostat To Induce Apoptosis In Leukemiamentioning

confidence: 99%