Current Pharmaceutical Design, Volume 7, No. 13, 2001
Tubulin-Interacting Agents
Modifications in the « upper » or
Velbenamine Part of the Vinca Alkaloids have Major Implications for Tubulin
Interacting Activities Pp.
1181-1197
Jacques Fahy
[Abstract] [Purchase Issue/Articles]
Bridget T. Hill
[Abstract]
Physiochemical Aspects of Tubulin-Interacting
Antimitotic Drugs Pp.
1213-1228
J.J.Correia and S.Lobert
[Abstract] [Purchase Issue/Articles]
General and Recent Aspects of the Chemistry and Structure Activity Relationships
of Taxoids Pp. 1229-1249
Francoise
Gueritte
[Abstract] [Purchase Issue/Articles]
Preclinical Evaluation of New Taxoids Pp. 1251-1257
M.-C.Bissery
[Abstract] [Purchase Issue/Articles]
Cryptophycins: A Novel Class of Potent Antimitotic Antitumor Depsipeptides Pp. 1259-1276
Chuan Shih and
Beverly A.Teicher
[Abstract] [Purchase Issue/Articles]
The Epothilones, Eleutherobins, and Related Types of Molecules Pp. 1277-1290
Shawn
j.Stachel, Kaustav Biswas and Samuel J. Danishefsky
[Abstract] [Purchase Issue/Articles]
Spongistatins as Tubulin Targeting Agents Pp. 1291-1296
F.M.Uckun,
C.Mao, S.-T.Jan, H.Huang, A.O.Vassilev, C.S.Navara and R.K.Narla
[Abstract] [Purchase Issue/Articles]
Epilogue Pp. 1297-1304
Jacques Fahy
and Bridget T. Hill
[Abstract] [Purchase Issue/Articles]
[Back to top] [Purchase
Issue/Articles]
Modifications in the « upper » or Velbenamine Part of the Vinca Alkaloids
have Major Implications for Tubulin Interacting Activities
Vinca alkaloids
represent a chemical class of major interest in cancer chemotherapy. The lead
compounds vinblastine and vincristine have been employed in clinical practice
for more than thirty years and remain widely used to this day. Several hundred
derivatives have been synthesised and evaluated for their pharmacological
activities, the majority being modified in the vindoline moiety, bearing
several reactive centers. These efforts led to the identification of the amido
derivative vindesine, registered in Europe in 1980 and now available in several
countries. Then novel chemistry permitted the semisynthesis of derivatives modified in
the velbenamine or
« upper » part of the molecule, creating a new potential in
the Vinca alkaloids medicinal chemistry: as a result, vinorelbine, obtained by
C’ ring contraction of anhydrovinblastine, and is now marketed worlwide.
Several strategies aimed at the total synthesis of vinblastine derivatives have
been investigated, giving the opportunity to design rationaly certain
compounds. Modifications in the D’ ring appeared to induce dramatic changes in
the tubulin interactions. These observations have been confirmed recently by
the identification of unprecedented pharmacological properties exerted by the
novel fluorinated Vinca alkaloid, vinflunine. This review will focus more specifically
on derivatives which have been modified in the velbenamine part, with the aim
of inducing different chemical and pharmacological properties.
Bridget T. Hill
The pharmacological profile of vinflunine, a novel bi-fluorinated derivative of vinorelbine is summarised. Detailed comparisons, based on in vitro and in vivo experimental preclinical data, of vinflunine with its parent molecule and the classic Vinca alkaloids, exemplified by vincristine or vinblastine, have revealed certain qualitative and quantitative differences between these first and second generation Vincas. Evidence is gradually accruing indicating that certain more subtle mechanistic differences exist in relation to the precise interactions of these individual molecules with cellular microtubules involving, for example, their suppression of microtubule dynamics. It is tempting, but premature, to suggest that these may be associated with the markedly superior in vivo antitumour activity of vinflunine documented in a series of murine and human xenografted tumour models. The in vivo antivascular effects of vinflunine, identified at doses below those required for optimal antitumour activity, coupled with the demonstrated potential value of vinflunine as a component of combination regimens, together with the finding that resistance to vinflunine was generated far less readily than to vinorelbine, augur well for the ongoing clinical development of this new agent. Finally, it is proposed that as our knowledge of the basic events involved in initiation and completion of mitosis and in defining the precise, yet multifacted, functions of microtubules increases, alternative intracellular targets will be identified. Such targets may prove suitable for pharmacological exploitation and more effective antimitotic antitumour agents will undoubtedly emerge. However, whether these will be third generation Vincas or molecules with quite different structures remains an open question
[Back to top] [Purchase
Issue/Articles]
Physiochemical Aspects of Tubulin-Interacting Antimitotic Drugs
J.J.Correia and S.Lobert
(250 words): A diverse group of natural biological compounds bind to microtubules and suppress microtubule dynamics. Here we review the mechanism of microtubule assembly and dynamics as well as structural features that are important for nucleotide binding, GTP hydrolysis and stabilization of longitudinal and lateral protofilament contacts. Specific emphasis is placed upon the polar structure of the microtubule, the exposure of the nucleotide hydrolysis site at the + end and the conformational and configurational plasticity of the microtubule lattice. These features have important implications for the mechanism of dynamic instability and the disruptive action of antimitotic drugs. We then discuss the various classes of tubulin binding drugs emphasizing their site and mode of binding as well as the structural and energetic basis for their effects on microtubule assembly and dynamics. A common feature of tubulin-interacting compounds is a linkage to assembly, either the stabilization of a microtubule lattice by compounds like taxol or epothilone A, or the preferential formation of alternate lattice contacts and polymers at microtubule ends by compounds like colchicine, vinca alkaloids and cryptophycin-52. Finally, we explore the likely possibility that these drugs also disrupt the regulation of microtubule dynamics. Future generations of these compounds may be selectively developed to directly target the proteins that regulate mitotic spindle dynamics
[Back to top] [Purchase
Issue/Articles]
General and Recent Aspects of the Chemistry and Structure Activity Relationships of
Taxoids
Francoise Gueritte