. Studies on the total synthesis and evaluation of antitumor antibiotics including (1) fendleridine, (2) lycorine, (3) pancratistatin, (4) (-)-vindoline, (5) an extensive library of ningalin derivatives as multidrug resistant (MDR) reversal drugs, (6) bleomycin derivatives, (7) indolocarbazoles including rebeccamycin, (8) cordytropolone, and (9) sultriecin and key structural analogues are detailed. In the course of the studies, the investigation, development, and implementation of: (1) heteroaromatic azadiene Diels- Alder reactions, (2) the LUMOdiene-controlled Diels-Alder reactions of N-sulfonyl-1- azadienes, (3) the thermal reactions of cyclopropenone ketals including those of reversibly generated p-delocalized singlet vinylcarbenes, and (4) tandem Diels- Alder/1,3-dipolar cycloadditions of 1,3,4-oxadiazoles will be pursued and provide the opportunity to comprehensively extend past studies. The proposed studies include the examination of antitumor compounds that mediate their cellular effects through selective target protein (e.g. PP2A, Pgp) or sequence selective DNA binding and provide well-defined problems on the design, preparation, and evaluation of synthetic, mechanism based analogues in which fundamental studies of the structural features responsible for protein or DNA binding affinity, selectivity, and functional reactivity may be addressed.
New insights into new classes of drugs for the treatment of cancer and methods for their preparation will emerge from the proposed studies.
|Morin, Matthew D; Wang, Ying; Jones, Brian T et al. (2018) Diprovocims: A New and Exceptionally Potent Class of Toll-like Receptor Agonists. J Am Chem Soc 140:14440-14454|
|Wang, Ying; Su, Lijing; Morin, Matthew D et al. (2018) Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti-PD-L1 to eliminate melanoma in mice. Proc Natl Acad Sci U S A 115:E8698-E8706|
|Glinkerman, Christopher M; Boger, Dale L (2018) Synthesis, Characterization, and Rapid Cycloadditions of 5-Nitro-1,2,3-triazine. Org Lett 20:2628-2631|
|Radakovic, Aleksandar; Boger, Dale L (2018) High expression of class III ?-tubulin has no impact on functional cancer cell growth inhibition of a series of key vinblastine analogs. Bioorg Med Chem Lett 28:863-865|
|Lukesh 3rd, John C; Carney, Daniel W; Dong, Huijun et al. (2017) Vinblastine 20' Amides: Synthetic Analogues That Maintain or Improve Potency and Simultaneously Overcome Pgp-Derived Efflux and Resistance. J Med Chem 60:7591-7604|
|Yang, Shouliang; Sankar, Kuppusamy; Skepper, Colin K et al. (2017) Total synthesis of a key series of vinblastines modified at C4 that define the importance and surprising trends in activity. Chem Sci 8:1560-1569|
|Allemann, Oliver; Cross, R Matthew; Brütsch, Manuela M et al. (2017) Key analogs of a uniquely potent synthetic vinblastine that contain modifications of the C20' ethyl substituent. Bioorg Med Chem Lett 27:3055-3059|
|Quiñones, Ryan E; Glinkerman, Christopher M; Zhu, Kaicheng et al. (2017) Direct Synthesis of ?-Aminoenals through Reaction of 1,2,3-Triazine with Secondary Amines. Org Lett 19:3568-3571|
|Boger, Dale L (2017) The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry-Biology Interface. J Org Chem 82:11961-11980|
|Carney, Daniel W; Lukesh 3rd, John C; Brody, Daniel M et al. (2016) Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer-dimer interface. Proc Natl Acad Sci U S A 113:9691-8|
Showing the most recent 10 out of 102 publications