Two series of arylmethylidene derivatives of imidazothiazolotriazinone differing in the structure of the imidazothiazolotriazine fragment were synthesized and their antiproliferative activity and effect on tubulin polymerization were evaluated. Some of the synthesized derivatives showed a significant antiproliferative effect, among which (Z)-7-(2,4-dichlorobenzylidene)-1,3-diethyl-1,3a,4,9a-tetrahydroimidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-2,8(3H,7H)-dione 2n exhibited the highest antiproliferative activity. The GI50 values of the compound against 56 of the 58 cell lines were 19.4-87.8 nM; against the remaining 2 cell lines, they were 0.544-1.29 µM. Moreover, further mechanism analysis demonstrated that 2n caused G2/M arrest, induced cell apoptosis in K562 cells and blocked tubulin polymerization in the same way as colchicine.
Highly diastereoselective methods for the synthesis of two series of regioisomeric polynuclear dispyroheterocyclic compounds with five or six chiral centers, comprising moieties of pyrrolidinyloxindole and imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine of linear structure or imidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine of angular structure, have been developed on the basis of a [3+2] cycloaddition of azomethine ylides to functionalized imidazothiazolotriazines. Depending on the structure of the ethylenic component, cycloaddition proceeds as an anti-exo process for linear derivatives, while cycloaddition to angular ones resulted in a syn-endo diastereomer. Novel pathways of isomerization for the synthesized anti-exo products upon treatment with sodium alkoxides have been found, which resulted in two more series of diastereomeric dispiro[imidazothiazolotriazine-pyrrolidin-oxindoles] inaccessible with the direct cycloaddition reaction. For the first series, the inversion of the configuration of one stereocenter, i.e., C-4' atom of the pyrrolidine cycle, (epimerization) was established. For the second one, configuration of the obtained diastereomer formally corresponded to the syn-endo approach of the azomethine ylide in the case of cycloaddition to the ethylenic component.
Oxindoles , Isomerism , Stereoisomerism , Cycloaddition Reaction
A series of imidazo[4,5-e][1,3]thiazino[2,3-c][1,2,4]triazines was synthesized via a cascade sequence of hydrolysis and skeletal rearrangement of imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazin-7(8H)-ylidene)acetic acid esters in methanol upon treatment with excess KOH. Imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazin-6(7H)-ylidene)acetic acid esters are also suitable substrates for the reaction. In this case hydrolysis and thiazole ring expansion were accompanied with the change of the thiazolotriazine junction type from thiazolo[3,2-b][1,2,4]triazine to thiazino[2,3-c][1,2,4]triazine.
A simple method for the synthesis of water-soluble potassium 3-[(imidazotriazin-3-yl)thio]-2-oxoquinoline-4-carboxylates was developed based on a new reversible transformation of oxindolylidene derivatives of imidazothiazolotriazine that results from their treatment with potassium hydroxide. The antiproliferative activity of the synthesized compounds was evaluated against 58 cell lines and compared with oxindolylidene derivatives of imidazothiazolotriazine. Quinoline derivatives 3 demonstrated high activity with average GI50 values of <10 µM which are comparable or higher than those of the oxindolylidene imidazothiazolotriazines. Compound 3a, with a pent-3-yl substituent at the nitrogen atom of the quinoline fragment, possessed the highest antiproliferative activity with an average GI50 value of 1.71 µM. The GI50 values of compound 3a against 52 of the 58 cell lines were <1 µM; against the remaining 6 of the 58 cell lines, they were in the range 1.21-39.2 µM.
Methods for the synthesis of two types of isomeric dispirocompounds based on imidazothiazolotriazine and pyrrolidineoxindole, differing in the structure of imidazothiazolotriazine fragment, namely, linear dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3'-pyrrolidine- 4',3â³-indolines] and angular dispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3'-pyrrolidine-4',3â³-indolines] were proposed. The first method relies on a 1,3-dipolar cycloaddition of azomethine ylides generated in situ from paraformaldehyde and N-alkylglycine derivatives to the corresponding oxindolylidene derivatives of imidazothiazolotriazine. The cycloaddition leads to a mixture of two diastereomers resulted from anti- and syn-approaches of azomethine ylide in approximately a 1:1 ratio, which were separated by column chromatography. Another method consists in rearrangement of linear dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3'-pyrrolidine-4',3â³-indolines] into hitherto unavailable angular dispiro[imidazo[4,5-e]thiazolo[2,3-c]-[1,2,4]triazine-7,3'-pyrrolidine-4',3â³-indolines] upon treatment with KOH. It was found that the anti-diastereomer of linear type underwent rearrangement into the isomeric angular syn-diastereomer, while the rearrangement of the linear syn-diastereomer gave the angular anti-diastereomer.
Spiro Compounds , Thiosemicarbazones , Spiro Compounds/chemistry , Thiosemicarbazones/chemistry , Pyrrolidines/chemistry , Triazines
Condensation of 1,3-diethyltetrahydroimidazo[4,5-е]thiazolo[3,2-b][1,2,4]triazine-2,7-dione with isatins followed by framework rearrangement in the thiazolotriazine moiety was used to synthesize two new series of oxindolylidenetetrahydroimidazo[4,5-е]thiazolo- [3,2-b][1,2,4]triazine-2,7-diones and oxindolylidenetetrahydroimidazo[4,5-е]thiazolo[2,3-c][1,2,4]triazine-2,8-diones containing various substituents in the oxindole moiety. The obtained compounds were tested for antiproliferative activity. The greatest activity was observed in the case of 1-alkyl-7-methyloxindolylidene derivatives of imidazo[4,5-е]thiazolo[2,3-c]triazine, which not only inhibited the growth of more than half of the studied cell lines, but also caused cell death in the SF-539 cell line (central nervous system cancer, mean growth percent -7.82%) and MDA-MB-435 (melanoma, -30.97 and -13.64%). Supplementary Information: The online version contains supplementary material available at 10.1007/s10593-022-03125-3.
Two series of functionalized imidazothiazolotriazine derivatives were synthesized via the condensation of imidazo[4,5-e]-1,2,4-triazine-3-thiones with acetylenedicarboxylic acid dimethyl and diethyl esters (DMAD and DEAD) and subsequent base-catalyzed rearrangement of the obtained imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazines into regioisomeric imidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine derivatives.
An original method for the synthesis of 2-hydrazonoimidazo[4,5-d]thiazolone derivatives has been developed based on a one-pot acid-induced sequence of hydrazone formation from 3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazinones and aromatic aldehydes, triazine ring contraction to imidazolidine one, and Dimroth-type N/S-interchange of N-aminothioglycolurils formed in situ into 2-hydrazonoimidazo[4,5-d]thiazolones. 3-Phenylacroleine derivatives are also suitable substrates for the reaction with thioxoperhydroimidazotriazinones.
Highly diastereoselective methods for the synthesis of two different diastereomers of polynuclear dispiroheterocyclic compounds with five chiral centers comprising pyrrolidinyloxindole and imidazothiazolotriazine moieties (dispiro[imidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine-7,3'-pyrrolidine-2',3''-indoles]) have been developed on the basis of a dipolar cycloaddition of azomethine ylides to benzylidene derivatives of imidazothiazolotriazines and an alkali-induced rearrangement of the thiazolotriazine fragment. The different sequence of the cycloaddition and rearrangement stages allows us to perform the targeted synthesis of two diastereomerically pure products from the same starting compounds.
A series of tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7(1H, 6H)-diones were synthesized via the reaction of imidazotriazinethiones and bromoacetic acid followed by condensation with isatins. Amidine skeletal rearrangement of 3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7 (1H, 6H)-diones into 1,3a,4,9a-tetrahydroimidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine-2,8 (3H, 7H)-diones under KOH treatment has been studied. The influence of substituents at positions 1,3,3a,6,9a of imidazothiazolotriazine on the ability to undergo rearrangement was analyzed based on experimental data and theoretical calculations. Both imidazothiazolo[3,2-b]triazines and their rearrangement products were evaluated for their cytotoxic activity against rhabdomyosarcoma, A549, HCT116 and MCF7 human cancer cell lines by MTT assay. Among the derivatives, 1,3-diethyl-6-[1-(2-propyl)-2-oxoindolin-3-ylidene]-3,3a,9,9a-tetrahydroimidazo [4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7(1H, 6H)-dione 4i was found to have the highest antiproliferative activity toward the tested cell lines (4i: [Formula: see text], 2.29, 0.47 and [Formula: see text], respectively). The [Formula: see text] value of compound 4i against normal human embryonic kidney cells HEK293 was [Formula: see text], which appeared to be 6-41-fold higher than [Formula: see text] values of 4i against human cancer cells.
Imidazoles/chemistry , Imidazoles/pharmacology , Triazines/chemistry , Triazines/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , HEK293 Cells , Humans , Jurkat Cells
An effective and highly regio- and diastereoselective one-pot method for the synthesis of new polynuclear dispiroheterocyclic systems with five stereogenic centers (dispiro[imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-6,3'-pyrrolidine-2',3''-indoles]) comprising pyrrolidinyloxindole and imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine moieties has been developed. The method relies on a 1,3-dipolar cycloaddition of azomethine ylides generated in situ from isatin derivatives and sarcosine to 6-benzylideneimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7-diones.
