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Syntheses and Structure−Activity Relationships of Novel Nor-seco Taxoids

Ojima, Iwao ; Lin, Songnian ; Chakravarty, Subrata ; Fenoglio, Ivana ; Park, Young Hoon ; Sun, Chung-Ming ; Appendino, Giovanni ; Pera, Paula ; Veith, Jean M. ; Bernacki, Ralph J.

The Journal of Organic Chemistry, 03/1998, Vol.63(5), pp.1637-1645 [Peer Reviewed Journal]

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  • Title:
    Syntheses and Structure−Activity Relationships of Novel Nor-seco Taxoids
  • Author: Ojima, Iwao ; Lin, Songnian ; Chakravarty, Subrata ; Fenoglio, Ivana ; Park, Young Hoon ; Sun, Chung-Ming ; Appendino, Giovanni ; Pera, Paula ; Veith, Jean M. ; Bernacki, Ralph J.
  • Description: A series of novel nor-seco taxoids (4a-b, 5a-d, 6), including either a C-13 ester linkage or a C-13 amide linkage, was synthesized by means of the [Beta]-lactam synthon method using the coupling of (3R,4S)-l-acyl-[Beta]-lactams with properly protected nor-seco baccatin III derivatives (1, 2, 3) as the key step. Nor-seco baccatin Ill derivatives were prepared through oxidative cleavage of the A ring of 14[Beta]-hydroxy-10-deacetylbaccatin III followed by reduction, amination using Mitsunobu conditions, or reductive amination. Nor-seco taxoids with a C-13 ester linkage (4a-b) or a C-13 N-Me amide linkage (6) show reduced cytotoxicity against human cancer cell lines as compared with paclitaxel, but still retain a certain level of activity despite the destruction of the taxane A ring. However, none of the analogues with a C-13 N-H amide linkage (5a-d) exhibit appreciable activity ([IC.sub.50] > 1.0 [[micro[molar]. A restrained molecular dynamics study reveals the inability of 5a-d to attain the proposed bioactive conformation, which accounts for the loss of activity.
  • Is Part Of: The Journal of Organic Chemistry, 03/1998, Vol.63(5), pp.1637-1645
  • Identifier: ISSN: 0022-3263 ; E-ISSN: 1520-6904 ; DOI: http://dx.doi.org/10.1021/jo971953r
  • Subjects: Structure-activity Relationships (Pharmacology) -- Research ; Antineoplastic Agent Structure-activity Relationships ; Organic Compound Synthesis
  • Language: English
  • Source: American Chemical Society (via CrossRef)

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