Synthesis of o-isotoluenes, o-quinodimethanes, and benzoenynyl carbodiimides and their cyclizations to polycyclic and heterocyclic compounds

Treatment of alkenyldicyclohexylboranes with 1-lithio-5-butyl-3,4-nonadien-1-yne, derived from 5-butyl-3,4-nonadien-1-yne, followed by trimethyltin chloride and acetic acid furnished the corresponding o-isotoluenes in a single operation. The reaction proceeded through an initial formation of (Z)-diene-allenes, which underwent facile eletrocyclizations to produce o-isotoluenes.;Treatment of allenyldicyclohexylborane with 1-lithio-5,5-pentamethylene-3,4-pentadien-1-yne produced the organoborate complex, which on further treatment with trimethyltin chloride furnished a (Z)-1,2,4,6,7-octapentaene (enediallene) derivative in situ. The subsequent electrocyclic reaction then generated the corresponding o-quinodimethane attached with a dicyclohexylboryl group and a trimethyltin group. The resulting o-quinodimethane then underwent a [1,5]-sigmatropic hydrogen shift, and on subsequent oxidative workup and protonation gave the 4-(1-cyclohexenyl)-3-methylphenol (51%). The presence of a boron group and a tin group in the benzene ring of a reaction intermediate also provides handles to allow their transformations to an allyl substituent and an iodo substituent to produce a tetrasubstituted benzene ring (30%) in a single operation. Attempts to capture the o-quinodimethane intermediate with a carbon--carbon double bond intramolecularly afforded a tricyclic phenol in low yield (6%). A number of other o-quinodimethanes were also generated by using different combinations of organoboranes and 1-lithio-1-alkynes.;6H-Indolo[2,3-b]quinolines were synthesized from N-[2-(1-alkynyl)- phenyl]-N\u27-phenylcarbodiimides via a thermally-induced biradical-forming reaction. The Pd-catalyzed cross-coupling reaction between methyl 2-iodobenzoate and 1-alkynes furnished methyl 2-(1-alkynyl)benzoates, which were hydrolyzed to afford the corresponding benzoic acids. Treatment of the benzoic acids with diphenyl phosphorazidate produced the 2-(1-alkynyl)phenyl isocyanates. The subsequent aza-Wittig reactions with the iminophosphorane, derived from aniline and Ph3P·Br2 then gave the benzoenynyl carbodiimides. Thermolysis of the benzoenynyl carbodiimides in refluxing p-xylene at 138°C produced the corresponding 6H-indolo[2,3-b]quinolines. Similarly, thermolysis of the carbodiimides having two benzoenynyl carbodiimide moieties produced compounds having two indoloquinoline units connected at the 11 and the 11\u27 positions with either a three-carbon or a five-carbon tether. By using 1,4-phenylene diisocyanate for the aza-Wittig reaction with two equiv of the iminophosphorane followed by thermolysis furnished a compound (66%) having two indoloquinoline units incorporated in the seven fused rings.;The synthetic pathway to the 6H-indolo[2,3- b]quinolines was successfully adopted for preparation of the 5-aza anologues of ellipticine, a naturally occuring alkaloid having potent anti-cancer properties. This approach, which constructs the B and the C rings in one step, is an efficient route in producing the aza analogues of the ellipticine family of antitumor alkaloids

Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

Malaria is a devastating tropical disease, claiming approximately 627 000 lives in 2020. Due to the appearance of resistance towards artemisinin-based therapies, the discovery of novel treatments are of paramount importance. The indoloquinoline natural products cryptolepine, neocryptolepine and isocryptolepine, first discovered in the extracts of the African bush plant Cryptolepis sanguinolenta, have been found to exhibit potent antimalarial properties. More-over, several functionalized derivatives of these compounds have shown great promise as antiplasmodial agents. The indoloquinoline alkaloids have also been found to possess significant antiproliferative and antimicrobial properties, making them ideal targets for the development into novel drug candidates. The first project in this work details the application of a synthetic approach first developed by Helgeland and Sydnes to assemble various tetracyclic ring systems. The key synthetic strategies being a Suzuki-Miyaura cross-coupling reaction followed by a palladium-catalyzed intramolecular cyclization. Though the approach was unsuitable to construct all the intended target molecules, it furnished the unexpected pyridophenanthridine scaffold. By further investigating alternative protocols for the construction of indoloquinolines, a regiodivergent intermediate was discovered, which allowed for the synthesis of both novel pyridophenanthridineand pyridocarbazole scaffolds by utilizing two different reaction protocols. By subjecting this common intermediate to a diazotization-azidation-nitrene insertion approach, the novel pyrido-carbazoles could be furnished in excellent yields. The unexpected formation of a biquinoline bridged by an aniline during a Suzuki-Miyaura cross-coupling reaction, was deemed interesting for development into a transition metal complex for catalysis. Through a collaborative effort with Dr. Eugene Khaskin’s group at Okinawa Institute of Science and Technology, five quinoline/pyridine N,N,N ligands were designed and synthesized. The key synthetic tools utilized in their construction was either a sequential Suzuki-Miyaura cross-coupling reaction and Buchwald-Hartwig amination or reductive amination. A novel two-step approach for the synthesis of the natural product neocryptolepine from commercially available bromoquinolines was developed. The key transformations being regioselective N-alkylations followed by a cascade Suzuki-Miyaura cross-coupling reaction andintramolecular nucleophilic C-N bond formation. The scope and limitations for the novel protocol was evaluated through the preparation of 24 neocryptolepine derivatives, bearing a diverse range of functional groups, where electron-withdrawing group substitutions were generally superior. It became apparent that it would also be possible to prepare a library of indolo[3,2-c]quino-lines from the same starting material as the newly devised strategy to produce neocryptolepines. By utilizing a reaction sequence consisting of a Suzuki-Miyaura cross-coupling reaction, installation of an azido moiety and finally photochemical cyclization, this goal was realized, producing a total of 19 indoloquinolines. This protocol was less robost towards substrate functionalizations than the neocryptolepine approach, with no apparent trend concerning electron-withdrawing and electron-donating groups being apparent. The photochemical cyclization was hypothesized to proceed via the formation of a reactive singlet nitrene intermediate. Finally, a selection of the prepared tetracyclic compounds assembled during this work was evaluated for their antiplasmodial, antiproliferative and antimicrobial activities by the help of various external collaborators. The most successful compound was revealed to be the novel pyridophenanthridines, displaying more potent antiproliferative activities than doxoru-bicin against human prostate cancer (IC50= 24 nM). The novel pyridocarbazoles moreover showed excellent inhibition of biofilm formation, with the potential to be developed into a dualanticancer-antimicrobial agent. Of all the tested compounds, only N-methylated pyridocar-bazole was found to contain any significant activity against the evaluated Plasmodium falci-parumstrain. The antimicrobial assays revealed the importance of the inclusion of a methylgroup for activity, but not strictly in the form of an N-methyl unit, which is the general concensus in the literature thus far. Further, chlorinated indoloquinolines were revealed to contain excellent antimicrobial activity against both Gram-positive and Gram-negative bacterial celllines

Diazinszármazékok szintézise; szerkezet-reaktivitás és szerkezet-biológiai hatás összefüggések vizsgálata = Synthesis of diazine derivatives; studies of structure-reactivity and structure-biological activity relationships

1. A terc-amino effektus 2. típusa amino(vinil)-diazinok körében: i) intramolekuláris ii) a vinil és aminoszubsztituensek geometriája és sztereoelektronos hatása jelentős iii) mikrohullámú besugárzással és/vagy oldószer nélkül magas hőmérsékleten kitűnő a konverzió. 2. Jód- és más halopiridazinokból Pd-katalizált reakciókkal policiklusos gyűrűrendszereket kaptunk. 3. Egy új jelentős antimaláriás hatású cryptolepin izomert állítottunk elő. Néhány jelentős SSAO enzimgátló molekulát szintetizáltunk. | 1. Type 2 tert.-amino effect in amino(vinyl)-diazines: i) is intramolecular ii) it is influenced significantly by the geometry and stereoelectronic effect of vinyl and amino substituents iii) excellent conversion could be achieved under microwave and/or solvent-free conditions. 2. The mechanism of formation of monoiodopyridazines from dihalopiridazines was investigated, and Pd-catalyzed reactions of iodo- and halopyridazines led to polycyclic systems. 3. A novel antimalarial cryptolepine isomer, isoneocryptolepine was synthesized in several steps based on a Suzuki reaction. Some new SSAO inhibitors were prepared

Organometallic indolo[3,2-c]quinolines versus indolo[3,2-d]benzazepines: synthesis, structural and spectroscopic characterization, and biological efficacy

The synthesis of ruthenium(II) and osmium(II) arene complexes with the closely related indolo[3,2-c]quinolines N-(11H-indolo[3,2-c]quinolin-6-yl)-ethane-1,2-diamine (L1) and N′-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine (L2) and indolo[3,2-d]benzazepines N-(7,12-dihydroindolo-[3,2-d][1]benzazepin-6-yl)-ethane-1,2-diamine (L3) and N′-(7,12-dihydroindolo-[3,2-d][1]benzazepin-6-yl)-N,N-dimethylethane-1,2-diamine (L4) of the general formulas [(η6-p-cymene)MII(L1)Cl]Cl, where M is Ru (4) and Os (6), [(η6-p-cymene)MII(L2)Cl]Cl, where M is Ru (5) and Os (7), [(η6-p-cymene)MII(L3)Cl]Cl, where M is Ru (8) and Os (10), and [(η6-p-cymene)MII(L4)Cl]Cl, where M is Ru (9) and Os (11), is reported. The compounds have been comprehensively characterized by elemental analysis, electrospray ionization mass spectrometry, spectroscopy (IR, UV–vis, and NMR), and X-ray crystallography (L1·HCl, 4·H2O, 5, and 9·2.5H2O). Structure–activity relationships with regard to cytotoxicity and cell cycle effects in human cancer cells as well as cyclin-dependent kinase (cdk) inhibition and DNA intercalation in cell-free settings have been established. The metal-free indolo[3,2-c]quinolines inhibit cancer cell growth in vitro, with IC50 values in the high nanomolar range, whereas those of the related indolo[3,2-d]benzazepines are in the low micromolar range. In cell-free experiments, these classes of compounds inhibit the activity of cdk2/cyclin E, but the much higher cytotoxicity and stronger cell cycle effects of indoloquinolines L1 and 7 are not paralleled by a substantially higher kinase inhibition compared with indolobenzazepines L4 and 11, arguing for additional targets and molecular effects, such as intercalation into DNA

Synthesis of benzocarbazoles, indoloquinolines and indolonaphthridines from thermolysis of benzoenynyl ketenimines and carbodiimides

The development of a general route to the N-[2-(1-alkynyl)phenyl]ketenimines (enyne-ketenimines) and N-[2-(1-alkynyl)phenyl]carbodiimides (enyne-carbodiimides) and their subsequent thermal behavior are described. Like enyne-allene and enyne-ketene systems, these enyne-hetereocumulenes undergo cycloaromatization through two competing biradical mechanisms under thermal conditions and therefore could serve as potential DNA cleaving agents. The resultant nitrogen-containing hetereocyclic compounds are also biologically interesting. The research described herein provides a easy access to the synthesis of benzo[b]carbazole, indoloquinoline and indolonaphthyridine alkaloids. In addition, the new synthetic strategies for these compounds are very versatile, providing access to a diverse array of analogs of these alkaloids

Neocryptolepine (cryprotackieine), a unique bioactive natural product: Isolation, synthesis, and profile of its biological activity

The widely varying different approaches to the total synthesis of the indoloquinoline alkaloid neocryptolepine are discussed. Aspects relating to the isolation of the natural product from Cryptolepis sanguinolenta, as well as its performance in various biological tests and spectroscopic studies involving the natural product, are also reviewed.Fil: Bracca, Andrea Beatriz Juana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Heredia, Daniel Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Larghi, Enrique Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Kaufman, Teodoro Saul. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentin

Structural Modifications of Nature-Inspired Indoloquinolines: A Mini Review of Their Potential Antiproliferative Activity

Cryptolepine, neocryptolepine and isocryptolepine are naturally occurring indoloquinoline alkaloids with various spectrum of biological properties. Structural modification is an extremely effective means to improve their bioactivities. This review enumerates several neocryptolepine and isocryptolepine analogues with potent antiproliferative activity against MV4-11 (leukemia), A549 (lung cancer), HCT116 (colon cancer) cell lines in vitro. Its activity towards normal mouse fibroblasts BALB/3T3 was also evaluated. Furthermore, structure activity relationships (SAR) are briefly discussed. The anticancer screening of neocryptolepine derivatives was performed in order to determine their cytotoxic and growth inhibitory activities across the JFCR39 cancer cell line panel

Antibacterial activity of alkaloids from Sida acuta

Sida acuta is a shrub indigenous to pantropical regions. The plant is widely used for its various pharmacological properties. Among compounds of pharmacological interest occurring in the plant, are indoloquinoline alkaloids. The aim of the present study was to investigate the antimicrobial activity of alkaloids of S. acuta from Burkina Faso. The alkaloids had a good antimicrobial activity against the test microorganisms. In the agar-well diffusion assay, highest inhibition zone diameters were recorded with Gram-positive bacteria. The broth microdilution assay gave minimal inhibitory concentration values ranging from 16 to 400 μg/ml and minimal bactericidal concentration values ranging from 80 to up to 400 μg/ml. The gas chromatography-mass spectrometry analysis of the same alkaloids led to the identification of cryptolepine and quindoline as the major components.Keywords: Cryptolepine, quindoline, indoloquinolines, antibacterial, Sida acut