Total synthesis of 6-deoxypladienolide D and Assessment of Splicing Inhibitory Activity in a Mutant SF3B1 cancer cell line.
A total synthesis of the natural product 6-deoxypladienolide D (1) has been achieved. Two noteworthy attributes of the synthesis are (1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and (2) the development of a scalable and cost-effective synthetic route to support drug discovery efforts. 6-Deoxypladienolide D (1) demonstrates potent growth inhibition in a mutant SF3B1 cancer cell line, high binding affinity to the SF3b complex, and inhibition of pre-mRNA splicing.
H3 Biomedicine, Inc. 300 Technology Square, Cambridge, Massachusetts 02139, United States.
Kenzo
K
Arai
Silvia
S
Buonamici
Betty
B
Chan
Laura
L
Corson
Atsushi
A
Endo
Baudouin
B
Gerard
Ming-Hong
MH
Hao
Craig
C
Karr
Kazunobu
K
Kira
Linda
L
Lee
Xiang
X
Liu
Jason T
JT
Lowe
Tuoping
T
Luo
Lisa A
LA
Marcaurelle
Yoshiharu
Y
Mizui
Marta
M
Nevalainen
Morgan Welzel
MW
O'Shea
Eun Sun
ES
Park
Samantha A
SA
Perino
Sudeep
S
Prajapati
Mingde
M
Shan
Peter G
PG
Smith
Parcharee
P
Tivitmahaisoon
John Yuan
JY
Wang
Markus
M
Warmuth
Kuo-Ming
KM
Wu
Lihua
L
Yu
Huiming
H
Zhang
Guo-Zhu
GZ
Zheng
Gregg F
GF
Keaney
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor / Q000737:chemistry* / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012326:RNA Splicing / Q000187:drug effects*; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000037:antagonists & inhibitors* / Q000737:chemistry*
C000594754:6-deoxypladienolide D; D000970:Antineoplastic Agents; D004852:Epoxy Compounds; D018942:Macrolides; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human