Transformations of 3,4-bisindolylmaleimides with differently bonded indole and maleimide moieties under the action of protic acids: A quantum chemical study

Abstract

Intramolecular cyclization reactions of 3,4 bis(indol 3 yl)maleimides 1, 3 (indol 1 yl) 4 (indol 3 yl)maleimides 2, and 3,4 bis(indol 1 yl)maleimides 3 under the action of protic acids were studied in order to estimate the parameters of the interaction between protonated and unprotonated indole moieties. Geometric parameters, charge distributions, energy characteris tics, and information concerning the frontier orbitals of bisindolylmaleimides 1-3 were ob tained from density functional B3LYP/6 31G(d) quantum chemical calculations. Alternative pathways of protonation of bisindolylmaleimides with differently bonded indole and maleimide moieties were studied and pathways of cyclization of corresponding conjugated acids leading to polyannelated compounds were analyzed. All the key intermediates of the cyclization reactions correspond to stationary points on the potential energy surfaces (minima and transition states). Analysis of the potential energy surfaces revealed almost linear dependences of the activation energies of the cyclization reactions under study on the distances between the reaction centers, on the angle of approach of intramolecular electrophile, and on the energy gap (energy differ ence between frontier orbitals). The key role in the cyclization reactions is played by structural similarity between the starting indoleninium cations and the activated complexes of the reac tions under study.Research on the chemical properties and reactivity of 3,4 bisindolylmaleimides is of interest in connection with the fact that some compounds of this series and related indolo[2,3]carbazoles possess valuable biological proper ties. 1,2 Earlier, 3,4 it was shown that intramolecular cy clizations of 3,4 bis(indol 3 yl)maleimides 1, 3 (indol 1 yl) 4 (indol 3 yl)maleimides 2, and 3,4 bis(indol 1 yl)maleimides 3 under the action of protic acids proceed differently and result in different types of compounds. 3,4 Bis(indol 3 yl)maleimides 1 under acid catalysis con ditions and after dehydrogenation form indolo[2,3]carb azole derivatives 4 (Scheme 1). In the absence of oxidant (DDQ) intermediate 5 undergoes isomerization into aminophenylcarbazole 6 (see Scheme 1). Possible mecha nisms of the cyclization and isomerization of system 1 are shown in Scheme 2.Unlike 3,4 bis(indol 3 yl)maleimides 1, 3 (indol 1 yl) 4 (indol 3 yl)maleimides 2 and 3,4 bis(indol 1 yl)maleimides 3 under the action of protic acids undergo 2-4´ or 2-7´ cyclization to give 8b,9 dihydroin dolo [4´,3´:3,4,5]pyrrolo[3´,4´:6,7][1,4]azepino[1,2 a]in dol 1,3(2H,5H ) diones 7 or 9b,10 dihydroindo lo[1´,7´:4,5,6]pyrrolo[3´,4´:2,3][1,4]diazepino[1,7 a]in dol 1,3 diones 8, respectively (Scheme 3). Compounds 7 and 8 under the action of DDQ in toluene were converted to indolo[4´,3´:3,4,5]pyrrolo[3´,4´:6,7]azepino[1,2 a]in dol 1,3(2H,5H ) diones 9 and 1H indolo[1´,7´:4,5,6]pyr rolo[3´,4´:2,3][1,4]diazepino[1,7 a]indol 1,3(2H ) diones 10, respectively. Possible cyclization mecha nisms 3,4 are shown in Scheme 3.Since the cyclization reactions of differently fused bisind...

Synthesis of 4-substituted 3-[3-(dialkylaminomethyl)indol-1-yl]maleimides and study of their ability to inhibit protein kinase C-α, prevent development of multiple drug resistance of tumor cells and cytotoxicity

“…However, the distances between the ni trogen atoms of the side chain and the indole ring in com pound Bis I and in the aminomethyl derivatives obtained are close and are equal to 4.64 and 4.57 Å, respectively. 11 For the new compounds, their ability to inhibit PKC α a cell free test system, as well as cytotoxicity in the human leucosis cell line, and the ability to prevent activation of gene MDR1 under the action of antitumor drug Cytosar (cytosine β D arabinofuranoside) have been investigated. A relationship between the amount of radioactive phos phate transferred by the kinase from [γ 32 P]ATP to its protein substrate and the concentration of the inhibitor has been studied.…”

tert-Amino effect: the Meth-Cohn and Reinhoudt reactions (Review)

“…In the presence of strong acids, 2-(dialkylamino)-3-(indol-1-yl)maleimides 97 underwent cyclization to 1,4-diazepines 98 annelated to an indole ring [75,76]. Hydride ion transfer was shown [77] to be the rate-limiting step (32.9 kcal/mol) [78]. The intramolecular nature of this hydride transfer was confirmed by an experiment with a deuterated alkylamino group [75].…”

Cyclization of vicinally substituted heterocyclic analogs of 3,4-bis(indol-1-yl)maleimide under the action of protic acids: a quantum chemical study

“…In particular, replacement of the C=O group in position 2 of the maleimide moiety by a CH 2 group causes almost no increase in ΔE ≠ ; replace ment of the NH group in position 1 by an O or CH 2 fragments leads to a slight increase in ΔE ≠ compared to the ΔE ≠ value for the cyclization of indoleninium cation with undistorted maleimide moiety. 3 Contrary to this, replacement of the double bond in positions 3 and 4 by a single bond, as well as replacement of the maleimide moiety by a butenedione one (this is best noticeable for the 2-7´ cyclization) causes the energy ΔE ≠ to consider ably increase compared to the ΔE ≠ value for the cycliza tion of the system with undistorted maleimide moiety.…”

“…3 Namely, the distance between the reaction centers in the activated complex (R) is about 1.63 Å, the angle of approach of the internal electrophile in the activated complex (ϕ) is nearly 115°, the energy gap between the frontier orbitals (Δε) is 2.33 eV, and the charges on the electrophilic and nucleophilic atoms C(2) and C(7´) are +0.137 and -0.209, respectively.…”