Synthesis of structurally simplified analogues of pancratistatin: truncation of the cyclitol ring.
Pancratistatin is a phenanthridone-type natural product isolated from several plants of the Amaryllidaceae family. Its potent antiproliferative, antivascular, antiviral, and antiparasitic properties have attracted the attention of synthetic, biological, and medicinal chemists. Pancratistatin's low natural availability and complex structure have steered many of these research projects toward the preparation of its simplified synthetic analogues with useful levels of activity. In this work we have developed synthetic chemistry aimed at the preparation of pancratistatin analogues with a truncated cyclitol portion of the molecule. The described synthetic pathways are based on a highly anti-diastereoselective arylcuprate conjugate addition to gamma-alkoxy-alpha,beta-enoates and syn-selective azidation at the alpha-position of ester enolates. Analogues with the formally cleaved C3-C4 bond, and thus containing an open ring C, as well as a compound containing a truncated lactol moiety in lieu of the cyclitol, were prepared. Several of the analogues exhibited weak antiproliferative activity, with the highest potency observed in the case of the lactol analogue. From these results implications for the design of future pancratistatin analogues are discussed. Furthermore, the synthetic pathways can be used to construct pancratistatin-mimetic libraries, in which the cyclitol moiety is replaced by other cyclic motifs.
Manpadi
Madhuri
M
Department of Chemistry, New Mexico Institute of Mining and Technology, Socorro, New Mexico 87801, USA.
Kireev
Artem S
AS
Magedov
Igor V
IV
Altig
Jeff
J
Tongwa
Paul
P
Antipin
Mikhail Yu
MY
Evidente
Antonio
A
van Otterlo
Willem A L
WA
Kornienko
Alexander
A
D047151:Amaryllidaceae Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001386:Azides / Q000737:chemistry; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D054812:Cyclitols / Q000737:chemistry*; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019668:Liliaceae / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D047151:Amaryllidaceae Alkaloids; D000970:Antineoplastic Agents; D001386:Azides; D001688:Biological Products; D054812:Cyclitols; D007546:Isoquinolines; C044997:pancratistatin