Alkylthiocolchicines and n‐deacetyl‐alkylthiocolchicines and their antileukemic activity

Shiau, George T.; De, Kalyan Kumar; Harmon, Robert E.

doi:10.1002/jps.2600640415

Cited by 27 publications

(8 citation statements)

References 10 publications

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Section: Biological Results and Discussionmentioning

confidence: 99%

“…Colchicide (19) was originally reported to be a potent inhibitor of [3H] colchicine binding to tubulin. 18 In a subsequent paper, 19 was reported to be essentially inactive in inhibiting [3H]colchicine binding to tubulin and in the P388 in vivo mouse leukemia screen. 16 We have found that 19 is a reasonably potent inhibitor of [3H] colchicine binding to tubulin and of in vitro assembly of microtubules.…”

Section: Biological Results and Discussionmentioning

confidence: 99%

“…It is unclear why 19 Several points should be noted from the data in Table II. First, the electronic nature of the C-10 substituent appears to be of little importance in the efficacy of the ligand.…”

Section: Biological Results and Discussionmentioning

confidence: 99%

“…Attempts to hydrolyze 9demethoxy-9-tosylisocolchicine with 5% NaOH in water/ ethanol also resulted in ring contraction product as well as colchiceine. We have found that when the alkoxymagnesium compound is the nucleophile rather than the 7.9 13.2 (±1.7) 53.7 (±2.5) CH3 (10) 4.1 56.6 (±1.5) 96.7 (±9.9) CH2CH3 (11) 4.2 54.9 (±6.8) 96.5 (±9.4) CH2CH2CH3 (12) 3.5 41.7 (±1.5) 89.2 (±5.9) CH(CH3)2 (13) 4.2 44.9 (±5.4) 90.0 (±1.9) (CH2)3CH3 ( 14) 26 13.9 (±7.0) 24.7 (±5.8) CH2CH(CH3)2 (15) 8.5 13.4 (±1.9) 36.7 (±4.6) CH(CH2CH3)(CH3) (16) 10 19.6 (±5.7)…”

Section: Chemistrymentioning

confidence: 99%

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Synthesis and tubulin binding of novel C-10 analogs of colchicine

Staretz¹,

Bane²

1993

J. Med. Chem.

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A series of novel C-10 derivatives of colchicine have been prepared and evaluated for inhibition of in vitro microtubule assembly and of [3H]colchicine binding to tubulin. The C-10 substituent of colchicine was replaced by halogens, alkyl and alkoxy groups, and hydrogen. Many of these compounds are available by nucleophilic substitution of 10-fluoro-10-demethoxycolchicine (9) without concomitant formation of ring contraction products. Compound 9 is prepared by reaction of (diethylamino)sulfur trifluoride with colchiceine. Unlike most reactions of colchiceine, the colchicine rather than the isocolchicine regiosiomer is the predominant product of this reaction. It was found that modification of the C-10 substituent of colchicine had a relatively minor effect on the potency of the colchicinoids. The electronic nature of the substituent had no significant effect on the efficacy of the compound, indicating that hydrogen bonding or polar interactions between the C-10 substituent of colchicinoids and an amino acid in the colchicine binding site on tubulin are not present in the colchicine-tubulin complex. A decrease in activity was observed with increasing length of the alkyl chain bonded to the C-10 position, but potency was less affected when the alkyl groups were positioned in close proximity to the C-10 carbon of the tropone ring. It is concluded that the steric rather than the electronic properties of the C-10 substituent are the predominant determinants of activity in this series.

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Section: Biological Results and Discussionmentioning

confidence: 99%

Section: Biological Results and Discussionmentioning

confidence: 99%

Section: Biological Results and Discussionmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

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Synthesis and tubulin binding of novel C-10 analogs of colchicine

Staretz¹,

Bane²

1993

J. Med. Chem.

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“…To accommodate this reactivity, thiocolchicine derivatives with nucleophilic sites were prepared. The thiocolchicine system was chosen because, in contrast to the 10methoxy group in colchicine, the methylthio substituent is stable to reaction conditions which hydrolytically remove the N-acetyl group from colchicine (Shiau et al, 1975). The known thiocolchicine derivatives N-deacetylthiocolchicine (Iorio et al,198 l), 2-demeth ylt hiocolchicine (S harma and Brossi, 1983), and 3-demethylcolchicine (Rossner et al, 1981) were prepared.…”

Section: Synthesis and Characterization Of Photoafiniy Labelsmentioning

confidence: 99%

Synthesis and Evaluation of 2‐diazo‐3,3,3‐trifluoropropanoyl Derivatives of Colchicine and Podophyllotoxin as Photoaffinity Labels: Reactivity, Photochemistry, and Tubulin Binding

Hahn

Bane

Sundberg

1992

Photochem & Photobiology

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Derivatives of the tubulin polymerization inhibitors colchicine and podophyllotoxin bearing the photoreactive 2-diazo-3,3,3-trifluoropropanoyl (DTFP) group were synthesized for evaluation as potential photoaffinity labels of the tubulin binding site. All labels were assayed for their ability to inhibit tubulin polymerization, and N-DTFP-deacetylthiocolchicine was shown to competitively inhibit tubulin-colchicine binding with a Ki of 4-5 microM. The tubulin off-rate of this analog was similar to that of podophyllotoxin, rather than to the relatively irreversibly bound colchicine. Photochemical solvent insertion reactions of the labels were investigated. Radioactive samples of the two most active labels were prepared and used in initial protein-labeling experiments, during which the fractional occupancy of tubulin and extent of covalent incorporation were determined. A rearrangement of DTFP amides was encountered which is relevant to the utility of this moiety for use in synthesis of photoaffinity labels.

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(–)-(M,7S)-Colchicine and (–)-(M,7S)-10-Ethylthiocolchicide/Alkyne Cycloaddition Reactions: Synthesis of Novel Colchicine Derivatives by Consecutive [4+2] and [3+2] Cycloadditions

Brecht

Haenel

Seitz³

et al. 1998

Eur. J. Org. Chem.

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Cycloaddition reactions of the facially dissymmetric diene moiety of (–)‐(M,7S)‐colchicine (5) and (–)‐(M,7S)‐10‐ethylthiocolchicide (9) to various alkynes have been studied. With 5 and the dienophilic benzyne (3), dimethyl acetylenedicarboxylate (DMAD) (4) and cyclooctyne (6) as starting materials all cycloadditions could be realized with high regioselectivity at the 8,12‐positions of the alkaloid. The approach of the dienophiles preferentially occurred toward the syn π‐face of the diene. In contrast to the cycloaddition mode of 5 the ethylthiocolchicide 9 surprisingly reacted in a different manner. With benzyne as starting material a novel [3+2] cycloaddition of the thioenol ether moiety of 9 towards the dipolarophilic benzyne is supposed, affording the unexpected colchicide 10 after [1,5]H shift of the primarily formed cycloadduct followed by cleavage of the C–S linkage. With DMAD (4) and cyclooctyne (6) the reaction course is more complex. In a consecutive [4+2]/[3+2] cycloaddition (or vice versa) followed by a thermally induced cycloreversion of a not identified intermediate DMAD (4) gives rise to the polycyclic thiophene derivative 13 and the novel allocolchicinoid 14. In a similar way cyclooctyne (6) yielded three products, the thiophene‐annulated homobarrelenones 18 and 19 and the tetracyclic allocolchicinoid 21. The structures of the novel colchicine derivatives were assigned on the basis of spectral data, those of the cycloadducts 1 and 19 were verified by X‐ray crystallography. For the unprecedented formation of the various allocolchicinoids by consecutive [4+2]/[3+2] cycloadditions plausible reaction pathways are suggested, as far as possible. In addition the inhibitory effects on the tubulin polymerization reaction in vitro of 10, 14, and 21 are reported.

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Alkylthiocolchicines and n‐deacetyl‐alkylthiocolchicines and their antileukemic activity

Cited by 27 publications

References 10 publications

Synthesis and tubulin binding of novel C-10 analogs of colchicine

Synthesis and tubulin binding of novel C-10 analogs of colchicine

Synthesis and Evaluation of 2‐diazo‐3,3,3‐trifluoropropanoyl Derivatives of Colchicine and Podophyllotoxin as Photoaffinity Labels: Reactivity, Photochemistry, and Tubulin Binding

(–)-(M,7S)-Colchicine and (–)-(M,7S)-10-Ethylthiocolchicide/Alkyne Cycloaddition Reactions: Synthesis of Novel Colchicine Derivatives by Consecutive [4+2] and [3+2] Cycloadditions

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