Synthesis and biological activity of analogues of the antimicrotubule agent N,beta,beta-trimethyl-L-phenylalanyl-N(1)-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]- N(1),3-dimethyl-L-valinamide (HTI-286).
Hemiasterlin, a tripeptide isolated from marine sponges, induces microtubule depolymerization and mitotic arrest in cells. HTI-286, an analogue from an initial study of the hemiasterlins, is presently in clinical trials. In addition to its potent antitumor effects, 2 has the advantage of circumventing the P-glycoprotein-mediated resistance that hampers the efficacy of other antimicrotubule agents such as paclitaxel and vincristine in animal models. This paper describes an in-depth study of the structure--activity relationships of analogues of 2, their effects on microtubule polymerization, and their in vitro and in vivo anticancer activity. Regions of the molecule necessary for potent activity are identified. Groups tolerant of modification, leading to novel analogues, are reported. Potent analogues identified through in vivo studies in tumor xenograft models include one superior analogue, HTI-042.
Zask
Arie
A
Chemical and Screening Sciences, and Oncology Research,Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA. zaska@wyeth.com
Birnberg
Gary
G
Cheung
Katherine
K
Kaplan
Joshua
J
Niu
Chuan
C
Norton
Emily
E
Suayan
Ronald
R
Yamashita
Ayako
A
Cole
Derek
D
Tang
Zhilian
Z
Krishnamurthy
Girija
G
Williamson
Robert
R
Khafizova
Gulnaz
G
Musto
Sylvia
S
Hernandez
Richard
R
Annable
Tami
T
Yang
Xiaoran
X
Discafani
Carolyn
C
Beyer
Carl
C
Greenberger
Lee M
LM
Loganzo
Frank
F
Ayral-Kaloustian
Semiramis
S
D000588:Amines / Q000737:chemistry; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003500:Cyclization; D004952:Esters / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008744:Methylamines / Q000138:chemical synthesis / Q000737:chemistry; D051379:Mice; D008870:Microtubules / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D015394:Molecular Structure; D009369:Neoplasms / Q000473:pathology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D019289:Pyruvic Acid / Q000737:chemistry; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism
D000588:Amines; D004952:Esters; C473896:HTI-286; D008744:Methylamines; D009842:Oligopeptides; D010455:Peptides; D014404:Tubulin; D019289:Pyruvic Acid; C027451:methylamine