Synthesis and biological evaluation of aromatic analogues of conduritol F, L-chiro-inositol, and dihydroconduritol F structurally related to the amaryllidaceae anticancer constituents.
Pancratistatin is a potent anticancer natural product, whose clinical evaluation is hampered by the limited natural abundance and the stereochemically complex structure undermining practical chemical preparation. Fifteen aromatic analogues of conduritol F, l-chiro-inositol, and dihydroconduritol F that possess four of the six pancratistatin stereocenters have been synthesized and evaluated for anticancer activity. These compounds serve as truncated pancratistatin analogues lacking the lactam ring B, but retaining the crucial C10a-C10b bond with the correct stereochemistry. The lack of activity of these compounds provides further insight into pancratistatin's minimum structural requirements for cytotoxicity, particularly the criticality of the intact phenanthridone skeleton. Significantly, these series provide rare examples of simple aromatic conduritol and inositol analogues and, therefore, this study expands the chemistry and biology of these important classes of compounds.
Kireev
Artem S
AS
Department of Chemistry, New Mexico Institute of Mining and Technology, Socorro, New Mexico 87801, USA.
Nadein
Oleg N
ON
Agustin
Vincent J
VJ
Bush
Nancy E
NE
Evidente
Antonio
A
Manpadi
Madhuri
M
Ogasawara
Marcia A
MA
Rastogi
Shiva K
SK
Rogelj
Snezna
S
Shors
Scott T
ST
Kornienko
Alexander
A
D047151:Amaryllidaceae Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002384:Catalysis; D003500:Cyclization; D005434:Flow Cytometry; D005960:Glucosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007294:Inositol / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007546:Isoquinolines / Q000737:chemistry; D019169:Jurkat Cells / Q000187:drug effects; D019668:Liliaceae / Q000737:chemistry*; D015394:Molecular Structure; D012235:Rhodamines / Q000378:metabolism; D013329:Structure-Activity Relationship
D047151:Amaryllidaceae Alkaloids; D017304:Annexin A5; D000970:Antineoplastic Agents; D005960:Glucosides; D007546:Isoquinolines; D012235:Rhodamines; C417483:conduritol F; C022027:lissamine rhodamine B; D007294:Inositol; C044997:pancratistatin