Tyrphostin-like compounds with ubiquitin modulatory activity as possible therapeutic agents for multiple myeloma.
With the goal of developing small molecules as novel regulators of signal transduction and apoptosis, a series of tyrphostin-like compounds were synthesized and screened for their activity against MM-1 (multiple myeloma) cells and other cell lines representing this malignancy. Synthesis was completed in solution-phase initially and then adopted to solid-phase for generating a more diverse set of compounds. A positive correlation was noted between compounds capable of inducing apoptosis and their modulation of protein ubiquitination. Further analysis suggested that ubiquitin modulation occurs through inhibition of cellular deubiquitinase activity. Bulky groups on the sidechain near the α,β-unsaturated ketone caused a complete loss of activity, whereas cyclization on the opposite side was tolerated. Theoretical calculations at the B3LYP/LACV3P(∗∗) level were completed on each molecule, and the resulting molecular orbitals and Fukui reactivity values for C(β) carbon were utilized in developing a model to explain the compound activity.
Department of Experimental Therapeutics, M D Anderson Cancer Center, Houston, TX 77030, United States.
Zhenghong
Z
Peng
Ashutosh
A
Pal
Dongmei
D
Han
Shimei
S
Wang
David
D
Maxwell
Alexander
A
Levitzki
Moshe
M
Talpaz
Nicholas J
NJ
Donato
William
W
Bornmann
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D020032:Tyrphostins / Q000737:chemistry* / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism
D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020032:Tyrphostins; D025801:Ubiquitin; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C507924:JAK2 protein, human; D053614:Janus Kinase 2