title: Synthesis and SAR requirements of adamantane-colchicine conjugates with both microtubule depolymerizing and tubulin clustering activities.
abstract: A series of analogues of conjugate 1, combining an adamantane-based paclitaxel (taxol) mimetic with colchicine was synthesized and tested for cytotoxicity in a cell-based assay with the human lung carcinoma cell line A549. The most active compounds (10 EC(50) 2 ± 1.0 nM, 23 EC(50) 6 ± 1.4 nM, 26 EC(50) 5 ± 1.8 nM, 28 EC(50) 11 ± 1.7 nM, 30 EC(50) 4.8 ± 0.5 nM) were found to interfere with the microtubule dynamics in an interesting manner. Treatment of the cells with these compounds promoted disassembly of microtubules followed by the formation of stable tubulin clusters. Structure-activity relationships for the analogues of 23 revealed the sensitivity of both cytotoxicity and tubulin clustering ability to the linker length. The presence of adamantane (or another bulky hydrophobic and non-aromatic moiety) in 23 was found to play an important role in the formation of tubulin clusters. Structural requirements for optimal activity have been partially explained by molecular modeling.
authors.affiliation: Department of Chemistry, M V Lomonosov Moscow State University, 119992 Moscow, Russian Federation. olgaz@org.chem.msu.ru
authors.forename: Olga N
authors.initials: ON
authors.lastname: Zefirova
authors.forename: Evgeniya V
authors.initials: EV
authors.lastname: Nurieva
authors.forename: Dmitrii V
authors.initials: DV
authors.lastname: Shishov
authors.forename: Igor I
authors.initials: II
authors.lastname: Baskin
authors.forename: Fabian
authors.initials: F
authors.lastname: Fuchs
authors.forename: Heiko
authors.initials: H
authors.lastname: Lemcke
authors.forename: Fabian
authors.initials: F
authors.lastname: Schröder
authors.forename: Dieter G
authors.initials: DG
authors.lastname: Weiss
authors.forename: Nikolay S
authors.initials: NS
authors.lastname: Zefirov
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Kuznetsov
mesh_terms: D000218:Adamantane / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014404:Tubulin; D017239:Paclitaxel; D000218:Adamantane; D003078:Colchicine