Synthesis of New Didemnin B Analogs for Investigations of Structure/Biological Activity Relationships

Mayer, Scott C.; Ramanjulu, Joshi M.; Vera, Matthew D.; Pfizenmayer, Amy J.; Joullié, Madeleine M.

doi:10.1021/jo00097a022

Cited by 65 publications

(46 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A similar result was reported by Mayer et al 59 who reported that didemnin B and several analogs were immunosuppressive in the LAF assay at nanomolar concentrations, but that cell viability was intact. LeGrue et al 49 also con®rmed intact cell viability after in vitro treatment by didemnin B using the trypan blue dye exclusion method.…”

Section: ±46supporting

confidence: 88%

“…99 Other changes to the proline residue were found to have important consequences. Mayer et al 59 reported that replacement of the Pro 8 of didemnin B with trans-4-hydroxyproline caused a drop in cytotoxicity and a two to three order of magnitude decrease in in vitro immunosuppressive activity, demonstrating again that the nature of this residue is important. Substitution of Pro 8 with 3,4-dehydroproline showed a tenfold increase in cytotoxicity and a twofold increase in immunosuppressive activity.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Natural products as probes of cell biology: 20 years of didemnin research

Vera

Joullié

2002

Medicinal Research Reviews

Self Cite

143

109

View full text Add to dashboard Cite

The discovery of the didemnin family of marine depsipeptides launched an exciting and intriguing chapter in natural product chemistry. The unusual structure of the didemnin congeners has led to several total syntheses by research groups from around the world. The impressive in vitro and in vivo biological activities of the didemnins resulted in the first human clinical trials in the U.S. of a marine natural product against cancer, and additional clinical trials of a second-generation didemnin, dehydrodidemnin B (aplidine), are underway. As we mark the 20-year anniversary of the discovery of the didemnins, this class of natural products continues to stimulate active research in fields ranging from synthetic and medicinal chemistry to clinical oncology and cell biology. While some progress was made in dissecting the molecular mechanism of action and in establishing structure-activity relationships, there are still more questions than answers. This review covers the recent didemnin literature, highlighting the work directed towards understanding how this group of natural products interact with fundamental processes such as cell proliferation, protein biosynthesis, and apoptosis. The didemnin field illustrates how natural product chemistry may be used as a critical tool for the study of cell biology.

show abstract

Section: ±46supporting

confidence: 88%

mentioning

confidence: 99%

Natural products as probes of cell biology: 20 years of didemnin research

Vera

Joullié

2002

Medicinal Research Reviews

Self Cite

143

109

View full text Add to dashboard Cite

show abstract

“…Mayer et al [216] synthesized five analogs of didemnin B 176. The structural modifications were at the side chain of didemnin B. Didemnin B was chosen as it is the most active didemnin.…”

Section: Syntheses Of Didemnin Analogsmentioning

confidence: 99%

Macrocyclic N-Methylated Cyclic Peptides and Depsipeptides

Maharani

Sleebs

Hughes³

2015

Studies in Natural Products Chemistry

View full text Add to dashboard Cite

“…The use of proline derivatives as organocatalysts13 and as key building blocks of many pharmaceuticals and natural products14 ensures its status as a privileged structural motif. Chiral 2,3-dehydroproline (3-pyrroline) products commonly originate from natural 3-hydroxy proline,15 a neglected family of chiral proline products emerged as an ideal target for our new methodology. Retrosynthetic analysis for 2,5-dihydropyrrolidine 15 (Scheme 2) suggests that the chiral vinyl aziridine ring expansion substrate ( 14 ) should originate from a Darzens reaction16 between a bromo acetate ( 12 ) and a chiral conjugated Ellman type imine17 ( 13 ).…”

mentioning

confidence: 99%

Stereospecific Ring Expansion of Chiral Vinyl Aziridines

et al. 2011

View full text Add to dashboard Cite

In this report, it is demonstrated that chiral vinyl aziridines can be stereospecifically ring expanded. This synthetic approach allows controlled access to chiral 2,5-cis or 2,5-trans-3-pyrroline products from starting materials with the appropriate aziridine geometry. Twenty three ring expansion examples, most of which feature a stereospecific cyclization, are presented.A cursory review of the structural motifs of the top 200 top selling drugs 1 reveals that around 90% contain at least one nitrogen atom and approximately 65% are decorated with a heterocycle. Not surprisingly, the majority of these heterocycles are nitrogenous, with pyrrolidines a commonly occurring heterocyclic scaffold. Given the success of chiral pyrrolidines as important pharmaceutical building blocks it follows that a range of practical synthetic methods are needed 2 to provide access to any targeted structural and stereochemical pyrrolidine pattern.We have chosen to tackle the challenge of developing useful pyrrolidine forming methods by revisiting the ring expansion of vinyl aziridines, first reported by Atkinson. 3 Surprisinigly, despite the potential usefulness of converting a vinylaziridine into a 3-pyrroline, there had only been a single study focused on using metal catalysts to aid the rearrangement prior to our contribution to this field. 4 Oshima and coworkers found that tosylated dieneaziridines could be ring expanded in the presence of a palladium catalyst to the 3-pyrrolines. Both the N-tosyl group and the diene moiety were reported to be essential for the success of this rearrangement. Simple non-dienic vinyl aziridines did not ring expand, furnishing instead a complex mixture of products. In our recent report, we demonstrated that this significant substrate limitation could be solved using Cu(hfacac) 2 as a catalyst. 5 The substrate scope of this new transformation, which we demonstrated for a range of tosyl (Ts) and N-phthalimide (NPhth) protected vinyl aziridines, was shown to be quite broad. In this report we expand these investigations further and focus our attention on stereospecific vinyl aziridine ring expansions and application of this new methods towards accessing chiral pyrroline products.njardars@email.arizona.edu. Supporting Information Available Full experimental details for all new compounds reported in this article including X-ray data for compounds 15d, 15j, 15l, 21d and 21f are available free of charge via the Internet at http://pubs.acs.org. In order to maximize the synthetic potential of our method for preparing chiral pyrroline products, it is essential that reliable, asymmetric, convergent, and scalable routes be available to access the requisite starting materials (chiral vinyl aziridines). 6 The union of an imine and suitably activated nucleophile quickly emerged as the optimal approach (Scheme 1). The imine based retrosynthetic analysis is highlighted for chiral pyrroline 3, which we envisioned would originate from the copper catalyzed ring expansion of a trans-or cis-vinyl aziridine (4 and ...

show abstract

Synthesis of New Didemnin B Analogs for Investigations of Structure/Biological Activity Relationships

Cited by 65 publications

References 3 publications

Natural products as probes of cell biology: 20 years of didemnin research

Natural products as probes of cell biology: 20 years of didemnin research

Macrocyclic N-Methylated Cyclic Peptides and Depsipeptides

Stereospecific Ring Expansion of Chiral Vinyl Aziridines

Contact Info

Product

Resources

About