Synthesis and biological evaluation of novel non-racemic indole-containing allocolchicinoids

Shchegravina, Ekaterina S.; Maleev, Alexander A.; Ignatov, Stanislav K.; Gracheva, Yu. A.; Stein, Andreas; Schmalz, Hans‐Günther; Gavryushin, Andrei; Zubareva, Anastasiya A.; Svirshchevskaya, E. V.; Fedorov, Alexey Yu.

doi:10.1016/j.ejmech.2017.09.055

Cited by 25 publications

(14 citation statements)

References 37 publications

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“…However, its significant toxicity limited its use in cancer therapy. Fedorov and co‐workers recently reported a semi‐synthetic pyrrolo‐allocolchicine 49 derivative starting from naturally occurring (−)‐(a R ,7 S )‐colchicine 46 . The synthesis involved the Curtius rearrangement as a key step.…”

Section: Application Of the Curtius Rearrangement In Medicinal Chemistrymentioning

confidence: 99%

“…This was then converted to heterocyclic derivative 49 (Scheme ). This derivative showed cytotoxic properties at sub‐nanomolar concentration, efficiently arrested the cell cycle in the G 2 /M phase, and showed pronounced anti‐cancer activity compared to colchicine …”

Section: Application Of the Curtius Rearrangement In Medicinal Chemistrymentioning

confidence: 99%

“…[41] However,i ts significant toxicityl imited its use in cancer therapy.F edorov and co-workersr ecently reported a semi-synthetic pyrrolo-allocolchicine 49 derivative starting from naturallyo ccurring (À)-(aR,7S)-colchicine 46. [42] The synthesis involved the Curtius rearrangement as akey step. Bromination and base-catalyzed ring contraction provided 4-bromoallocolchicinic acid 47.I tw as subjected to the Curtius rearrangementi nt he presence of sodium azide providing the corresponding aniline 48 in 45 %y ield.…”

Section: Tubulin Binding Agentsmentioning

confidence: 99%

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The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

2018

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The Curtius rearrangement is the thermal decomposition of an acyl azide derived from carboxylic acid to produce an isocyanate as the initial product. The isocyanate can undergo further reactions to provide amines and their derivatives. Due to its tolerance for a large variety of functional groups and complete retention of stereochemistry during rearrangement, the Curtius rearrangement has been used in the synthesis of a wide variety of medicinal agents with amines and amine-derived functional groups such as ureas and urethanes. The current review outlines various applications of the Curtius rearrangement in drug discovery and medicinal chemistry. In particular, the review highlights some widely used rearrangement methods, syntheses of some key agents for popular drug targets and FDA-approved drugs. In addition, the review highlights applications of the Curtius rearrangement in continuous-flow protocols for the scale-up of active pharmaceutical ingredients.

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Section: Application Of the Curtius Rearrangement In Medicinal Chemistrymentioning

confidence: 99%

Section: Application Of the Curtius Rearrangement In Medicinal Chemistrymentioning

confidence: 99%

Section: Tubulin Binding Agentsmentioning

confidence: 99%

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The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

2018

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“…For this reason, new derivatives obtained through chemical modifications guided by structure-activity relations are intensively investigated. This research is aimed at reducing the colchicine toxicity and preserving the antimitotic and anticancer properties [12][13][14][15][16][17][18][19][20][21][22][23][24]. As it turns out, tubulin interacts with trimethoxyphenyl ring A and tropolone ring C, making the methoxy groups at C1, C2 and C10, as well as the C9-keto group, crucial for colchicine's antimitotic activity [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antiproliferative Screening Of Novel Analogs of Regioselectively Demethylated Colchicine and Thiocolchicine

et al. 2020

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Colchicine, a pseudoalkaloid isolated from Colchicum autumnale, has been identified as a potent anticancer agent because of its strong antimitotic activity. It was shown that colchicine modifications by regioselective demethylation affected its biological properties. For demethylated colchicine analogs, 10-demethylcolchicine (colchiceine, 1) and 1-demethylthiocolchicine (3), a series of 12 colchicine derivatives including 5 novel esters (2b–c and 4b–d) and 4 carbonates (2e–f and 4e–f) were synthesized. The antiproliferative activity assay, together with in silico evaluation of physicochemical properties, confirmed attractive biological profiles for all obtained compounds. The substitutions of H-donor and H-acceptor sites at C1 in thiocolchicine position provide an efficient control of the hydration affinity and solubility, as demonstrated for anhydrate 3, hemihydrate 4e and monohydrate 4a.

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“…Ring B appears to be responsible for the irreversible nature of colchicine binding to tubulin, although it may also contribute to its toxic effects [ 11 , 17 ]. Therefore, currently much interest has focused on structural modification of 1 in the hope of improving its anticancer activity [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives

Majcher

Klejborowska

Moshari

et al. 2018

Cells

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Microtubules are tubulin polymer structures, which are indispensable for cell growth and division. Its constituent protein β-tubulin has been a common drug target for various diseases including cancer. Colchicine has been used to treat gout, but it has also been an investigational anticancer agent with a known antimitotic effect on cells. However, the use of colchicine as well as many of its derivatives in long-term treatment is hampered by their high toxicity. To create more potent anticancer agents, three novel double-modified colchicine derivatives have been obtained by structural modifications in C-4 and C-10 positions. The binding affinities of these derivatives of colchicine with respect to eight different isotypes of human β-tubulin have been calculated using docking methods. In vitro cytotoxicity has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo and LoVo/DX). Computer simulations predicted the binding modes of these compounds and hence the key residues involved in the interactions between tubulin and the colchicine derivatives. Two of the obtained derivatives, 4-bromothiocolchicine and 4-iodothiocolchicine, were shown to be active against three of the investigated cancer cell lines (A549, MCF-7, LoVo) with potency at nanomolar concentrations and a higher relative affinity to tumor cells over normal cells.

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Synthesis and biological evaluation of novel non-racemic indole-containing allocolchicinoids

Cited by 25 publications

References 37 publications

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

Synthesis and Antiproliferative Screening Of Novel Analogs of Regioselectively Demethylated Colchicine and Thiocolchicine

Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives

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