Synthesis, modeling, and biological evaluation of anti-tubulin indole-substituted furanones.

Due to the central role of tubulin in various cellular functions, it is a validated target for anti-cancer therapeutics. However, many of the current tubulin inhibitors are derived from complex natural products and suffer from multidrug resistance, low solubility, toxicity issues, and/or the lack of multi-cancer efficacy. As such, there is a continued need for the discovery and development of new anti-tubulin drugs to enter the pipeline. Herein we report on a group of indole-substituted furanones that were prepared and tested for anti-cancer activity. Molecular docking studies showed positive correlations between favorable binding in the colchicine binding site (CBS) of tubulin and anti-proliferative activity, and the most potent compound was found to inhibit tubulin polymerization. These compounds represent a promising new structural motif in the search for small heterocyclic CBS cancer inhibitors.

Discovery of an indole-substituted furanone with tubulin polymerization inhibition activity.

Analogs of diarylpyrrolinone lead compound 1 were prepared and tested for anti-proliferative activity in U-937 cancer cells. Alterations of 1 focused on modifying the two nitrogen atoms: a) the pyrrolinone nitrogen atom was substituted with a propyl group or replaced with an oxygen atom (furanone), and b) the substituents on the indole nitrogen were varied. These changes led to the discovery of a furanone analog 3b with sub-micromolar anti-cancer potency and tubulin polymerization inhibition activity.

Synthesis and evaluation of the anti-proliferative activity of diaryl-3-pyrrolin-2-ones and fused analogs.

Analogs containing a central 3-pyrrolin-2-one core with different methoxyphenyl and/or indole substituents were prepared and tested for anti-proliferative activity in U-937 cells. The most efficacious analogs were non-rigid, (non-fused) contained methoxyaryl groups located at the 4-position, and contained either methoxyaryl or indole groups located at the 3-position. Both the number of methoxy groups contained in the substituents and the particular location of the indole rings with respect to the lactam carbonyl had significant affects on anti-proliferative activity. This work provides a framework to better understand structure-activity relationships for inducing anti-proliferative activity in diaryl heterocyclic scaffolds.

Synthesis of Benzo[a]carbazoles and an Indolo[2,3-a]carbazole from 3-Aryltetramic Acids.

A simple and flexible approach to 3-pyrrolin-2-one fused carbazoles is disclosed. The key step involves the BF3-mediated electrophilic substitution of indoles with N-alkyl-substituted 3-aryltetramic acids, which provides access to indole-substituted 3-pyrrolin-2-ones. Scholl-type oxidative cyclizations of these materials led to the formation of the corresponding 3-pyrrolin-2-one-fused benzo[a]carbazoles and indolo[2,3-a]carbazoles. This work represents the first synthesis of the benzo[a]pyrrolo[3,4-c]carbazol-3(8H)-one ring system, while the indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-one ring system is found in a number of biologically active compounds including the protein kinase C (PKC) inhibitor, staurosporine.

Preparation of dibenzo[e,g]isoindol-1-ones via Scholl-type oxidative cyclization reactions.

A flexible synthesis of dibenzo[e,g]isoindol-1-ones has been developed. Dibenzo[e,g]isoindol-1-ones represent simplified benzenoid analogues of biological indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-ones (indolocarbazoles), compounds that have demonstrated a wide range of biological activity. The synthesis of the title compounds involved tetramic acid sulfonates. Different aryl groups were introduced at C4 of the heterocyclic ring via Suzuki-Miyaura cross-coupling reactions. Finally, mild Scholl-type oxidative cyclizations mediated by phenyliodine(III) bis(trifluoroacetate) (PIFA) converted some of the latter compounds into the corresponding dibenzo[e,g]isoindol-1-ones. A systematic study of the oxidative cyclization revealed the following reactivity trend: 3,4-dimethoxyphenyl ≫ 3-methoxyphenyl > 3,4,5-trimethoxyphenyl > 4-methoxyphenyl ≈ phenyl. Overall, the oxidative cyclization required at least two methoxy groups distributed in the aromatic rings, at least one of which had to be located para to the site of the cyclization.

Synthesis of unsymmetrical 3,4-diaryl-3-pyrrolin-2-ones utilizing pyrrole Weinreb amides.

A regiocontrolled synthesis of unsymmetrical 3,4-diaryl-3-pyrrolin-2-ones has been achieved in three steps from 1,2-diaryl-1-nitroethenes with pyrrole-2-carboxamides (pyrrole Weinreb amides) serving as the key linchpin intermediates. Two different methods for the preparation of the requisite nitroalkenes were investigated: (1) modified Henry reaction between arylnitromethanes and arylimines; and (2) Suzuki-Miyaura cross-coupling reaction of 2-aryl-1-bromo-1-nitroethenes with arylboronic acids. Some difficulty was encountered in the preparation of arylnitromethanes, thus leading to the exploration of a cross-coupling strategy that proved more useful. A Barton-Zard pyrrole cyclocondensation reaction between 1,2-diaryl-1-nitroethenes and N-methoxy-N-methyl-2-isocyanoacetamide gave the corresponding pyrrole Weinreb amides, which were then converted into the desired 3-pyrrolin-2-ones in two steps. Overall, this method allowed for the construction of 3,4-diaryl-3-pyrrolin-2-ones with complete regiocontrol of the substituents with respect to the lactam carbonyl. The utility of this synthetic methodology was demonstrated by the preparation of eight unsymmetrical and symmetrical 3,4-diaryl-3-pyrrolin-2-ones including the N-H lactam analogue of the selective COX-II inhibitor, rofecoxib.

4-Phenyl-sulfon-yl-2-(p-tolyl-sulfon-yl)-1H,8H-pyrrolo-[2,3-b]indole.

The title compound, C(23)H(18)N(2)O(4)S(2), contains a pyrrolo group fused onto the plane of an indole ring with phenyl-sulfonyl and p-toluene-sulfonyl groups bonded to the indole and pyrrolo rings. The angles between the mean planes of the pyrrolo-indole ring and the phenyl-sulfonyl and p-toluene-sulfonyl rings are 73.7 (6) and 80.6 (0)°, respectively. The dihedral angle between the mean planes of the two benzene rings is 78.7 (4)°. In the crystal, both classical N-H⋯O and non-classical C-H⋯O inter-molecular hydrogen-bonding inter-actions are observed, as well as weak π-π inter-actions [centroid-centroid distances = 3.6258 (8) and 3.9298 (8) Å], which contribute to the stability of the packing.

Regiocontrolled synthesis of pyrrole-2-carboxaldehydes and 3-pyrrolin-2-ones from pyrrole Weinreb amides.

A regiocontrolled synthesis of 3,4-disubstituted pyrrole-2-carboxaldehydes was completed in two steps from acyclic starting materials. A Barton-Zard pyrrole synthesis between N-methoxy-N-methyl-2-isocyanoacetamide and alpha-nitroalkenes or beta-nitroacetates provided N-methoxy-N-methyl pyrrole-2-carboxamides (pyrrole Weinreb amides), which were converted into the corresponding pyrrole-2-carboxaldehydes by treatment with lithium aluminum hydride. A regioselective oxidation of the pyrrole-2-carboxaldehydes gave the corresponding 3,4-disubstituted 3-pyrrolin-2-ones.

Dendrimeric molecular transporters: synthesis and evaluation of tunable polyguanidino dendrimers that facilitate cellular uptake.

[reaction: see text] Nine fluorescently labeled structurally varied polyguanidino dendrimers based on diamino acid monomeric units were individually synthesized in an efficient, scalable sequence using a trifluoroacetamide protecting group-perguanidinylation strategy. While the dendrimers varied significantly in their ability to enter a human lymphocyte cell line, the best transporters out-performed an oligoarginine reference standard.