Synthetic mRNA splicing modulator compounds with in vivo antitumor activity.
We report our progress on the development of new synthetic anticancer lead compounds that modulate the splicing of mRNA. We also report the synthesis and evaluation of new biologically active ester and carbamate analogues. Further, we describe initial animal studies demonstrating the antitumor efficacy of compound 5 in vivo. Additionally, we report the enantioselective and diastereospecific synthesis of a new 1,3-dioxane series of active analogues. We confirm that compound 5 inhibits the splicing of mRNA in cell-free nuclear extracts and in a cell-based dual-reporter mRNA splicing assay. In summary, we have developed totally synthetic novel spliceosome modulators as therapeutic lead compounds for a number of highly aggressive cancers. Future efforts will be directed toward the more complete optimization of these compounds as potential human therapeutics.
Lagisetti
Chandraiah
C
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, MS 1000, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Pourpak
Alan
A
Goronga
Tinopiwa
T
Jiang
Qin
Q
Cui
Xiaoli
X
Hyle
Judith
J
Lahti
Jill M
JM
Morris
Stephan W
SW
Webb
Thomas R
TR
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004952:Esters / Q000737:chemistry; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D012326:RNA Splicing / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D012995:Solubility; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D002219:Carbamates; D004952:Esters; D012333:RNA, Messenger