Abstract:Synthesis of indolo[6,7-a]pyrrolo[3,4-c]carbazoles 1, a new class of cyclin D1/CDK4 inhibitors, by oxidation of the corresponding aryl indolylmaleimides 2, will be described. Two approaches to the synthesis of 2 were identified that required new methods for the synthesis of 7-substituted indole acetamides 3 and N-methyl (indol-7-yl)oxoacetates 6. The chemistry developed enabled introduction of functionality (-OR, NR(2)) at C(12) and N(13) facilitating structure-activity relationship (SAR) evaluation of this in… Show more
“…Several attempts of cyclization of 5 , using our previously described conditions, were unproductive. , Only the starting material and detriflated compound 4 were isolated whatever the reaction time and temperature, thus indicating a complete absence of insertion of the palladium entity in the C−OTf bond. Despite a reported successful condensation of 4-indolyl triflate at the position-2 of an indole derivative in the presence of Pd(OAc) 2 with dppe as a ligand and an excess of triethylamine at 110 °C, we were unable to apply these conditions to 5 to obtain the desired cyclized product.…”
Section: Chemistrymentioning
confidence: 98%
“…In addition, most of the aryl carbazoles designed so far for kinase inhibition are equipped with an unsubstituted maleimide, whereas in general the most cytotoxic compounds bear hydrophilic side chains. It is important to mention also that closely related (het)arylcarbazoles (type III ) have been described as inhibitors of cyclin D1/CDK4. , This strategy was previously adopted for granulatimide and isogranulatimide (Figure ) acting as G2 checkpoint inhibitors. − Cyclin-dependent kinases (CDKs) were also targeted with indolocarbazoles such as bis N -indolyl alkylated arcyriaflavins recently described as CDK1, CDK2, and CDK4 inhibitors. , In the NH maleimide series, indole versus (hetero)arylcarbazoles replacement represents also an interesting strategy. 1 Modifications of the indolocarbazole skeleton.…”
We here report the synthesis and biological evaluation of new phenylcarbazole derivatives designed as potential anticancer agents. Indole and hydroxyindole were used to generate three scaffolds that were successively exploited to introduce various substituents on the maleimide moiety. The synthesis includes a final intramolecular key Heck-type reaction, which was carried out with a triflate derivative or with a bromophenyl derivative. Each step was optimized and the complete chemical strategy is detailed. Several compounds showed a marked cytotoxicity against CEM human leukemia cells with IC(50) values in the 10-100 nM range. Precise structure-activity relationships were delineated. Cell cycle analysis, topoisomerase I inhibition, and interaction with DNA were evaluated, and inhibition of CDK activity was also investigated. Although binding of the drugs to DNA likely contributes to the cytotoxic action, the exact molecular targets of these molecules remain undiscovered. The efficient chemical routes reported here for the design of highly cytotoxic compounds provide novel opportunities to identify antitumor agents in the phenylcarbazole series.
“…Several attempts of cyclization of 5 , using our previously described conditions, were unproductive. , Only the starting material and detriflated compound 4 were isolated whatever the reaction time and temperature, thus indicating a complete absence of insertion of the palladium entity in the C−OTf bond. Despite a reported successful condensation of 4-indolyl triflate at the position-2 of an indole derivative in the presence of Pd(OAc) 2 with dppe as a ligand and an excess of triethylamine at 110 °C, we were unable to apply these conditions to 5 to obtain the desired cyclized product.…”
Section: Chemistrymentioning
confidence: 98%
“…In addition, most of the aryl carbazoles designed so far for kinase inhibition are equipped with an unsubstituted maleimide, whereas in general the most cytotoxic compounds bear hydrophilic side chains. It is important to mention also that closely related (het)arylcarbazoles (type III ) have been described as inhibitors of cyclin D1/CDK4. , This strategy was previously adopted for granulatimide and isogranulatimide (Figure ) acting as G2 checkpoint inhibitors. − Cyclin-dependent kinases (CDKs) were also targeted with indolocarbazoles such as bis N -indolyl alkylated arcyriaflavins recently described as CDK1, CDK2, and CDK4 inhibitors. , In the NH maleimide series, indole versus (hetero)arylcarbazoles replacement represents also an interesting strategy. 1 Modifications of the indolocarbazole skeleton.…”
We here report the synthesis and biological evaluation of new phenylcarbazole derivatives designed as potential anticancer agents. Indole and hydroxyindole were used to generate three scaffolds that were successively exploited to introduce various substituents on the maleimide moiety. The synthesis includes a final intramolecular key Heck-type reaction, which was carried out with a triflate derivative or with a bromophenyl derivative. Each step was optimized and the complete chemical strategy is detailed. Several compounds showed a marked cytotoxicity against CEM human leukemia cells with IC(50) values in the 10-100 nM range. Precise structure-activity relationships were delineated. Cell cycle analysis, topoisomerase I inhibition, and interaction with DNA were evaluated, and inhibition of CDK activity was also investigated. Although binding of the drugs to DNA likely contributes to the cytotoxic action, the exact molecular targets of these molecules remain undiscovered. The efficient chemical routes reported here for the design of highly cytotoxic compounds provide novel opportunities to identify antitumor agents in the phenylcarbazole series.
“…In continuation of their work devoted to the design of potent and selective cyclin D1/CDK4 inhibitors, workers at Lilly Research Laboratories investigated a series of [6,7-a]pyrrolo[3,4-c]carbazoles 111 substituted on the indolic nitrogens or on the indolic rings as well as other series 112 – 115 bearing different groups at N13 and C12 positions to improve aqueous solubility [57] (Figure 10). These compounds were prepared according to Faul’s synthetic scheme requiring new methods to access to 7-substituted indole acetamides and N -methyl(indol-7-yl)oxoacetates [58]. …”
Section: Replacement Of the Imidazole Ring (Unit E)mentioning
Granulatimide and isogranulatimide are alkaloids obtained from marine sources which have been shown to inhibit cell-cycle G2-checkpoint, targeting more particularly checkpoint 1 kinase (Chk1). At a structural level, they possess a characteristic pyrrolocarbazole framework also shared by the well-known rebeccamycin and staurosporine microbial metabolites which have been described to inhibit topoisomerase I and diverse kinases, respectively. This review reports precisely on the synthesis and kinase inhibitory activities of pyrrolocarbazole-based analogues of granulatimide.
“…Several indolocarbazole analogs have also been developed as very potent CDK4 inhibitors 29-31,33,35,36,39,40. For instance, naphyl[a]pyrolo[3,4-c]carbazole-5,7(6H, 12,H)-dione (NPCD) and isoquinolinyl[a]pyrrolo[34-c]carbazole (IQPC) have an IC 50 on CDK4 at a range of 45-75 nM while affecting other CDKs, such as CDK2, at much higher concentrations 31,35.…”
Introduction: Cyclin D1 (D1) binds to cyclin-dependent kinases (CDK) 4 or 6 to form a holoenzyme that phosphorylates the Rb protein to promote cell cycle progression from G1 to S phase. Therefore, targeting CDK4/6 may be a good strategy for chemotherapy of cancer. We performed a proof-of-principle study to determine the effect of Naphtho [2, 1-α] pyrrolo [3, 4-c] carbazole-5, 7 (6H, 12H)-dione (NPCD), a novel CDK4 inhibitor, on breast cancer cell lines.Methods: NPCD was synthesized and purified to over 99% purity verified by HPLC. MCF7, MB231, MCF15, T47D and GI101Ap human breast cancer cells were analyzed for the efficacy of NPCD with MTT and clonogenic assays, with FACS and staining for ethidium bromide and acridine orange for cell death and cell cycle profile. Western blot, reverse transcription and PCR were used for studies of gene expression, and co-immunoprecipitation for protein-complex formation.Results: MTT assay showed that NPCD caused growth arrest and apoptosis of MCF7, MDA-MB231, T47D, MCF15 and GI101Ap cells with an IC50 ranging between 3 to 8 µM given as a single dose. The growth arrest persisted for many days after cessation of the treatment, as shown in a clonogenic assay. NPCD could induce or reduce the D1 and CDK4 protein levels, depending on the cell line, but this effect was not correlated with its efficacy. Phosphorylation of D1 at Thr286 was decreased but it unexpectedly did not correlate with the change in D1 level in the cell lines studied. Phosphorylation of the Rb protein was decreased as expected whereas the p27kip1 protein level was decreased unexpectedly. Protein levels of p21cip1, CDK2 and cyclin E were also decreased in some, but not all, of the cell lines, whereas the mRNA levels of D1, CDK4, cyclin E, CDK2, p27kip1 and p21cip1 were increased in different cell lines.Conclusions: NPCD can cause long-lasting growth arrest and cell death of breast cancer cell lines at an IC50 of 3-8 µM. Decreased phosphorylation of Rb by D1-CDK4/6 and decreased p27kip1 protein level may be part of the underlying mechanism.
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