Synthesis of 6‐amino acid substituted 4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizines

In the presence of Na₂CO₃ (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐3‐(1,3‐dioxo‐butyl)oxymethyl‐1,2,3,4‐tetrahydrocarboline ( 1 ) were transformed into (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐3‐hydroxymethyl‐1,2,3,4‐tetrahydrocarboline ( 2 ), which were cyclized to (6S)‐3‐acetyl‐6‐hydroxymethyl‐4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizine ( 4 ), via(6S,12bS)‐ and (6S,12bR)‐3‐acetyl‐2‐hydroxyl‐6‐hydroxymethyl‐1,2,3,4,6,7,12,12b‐octahydro‐4‐oxoindolo[2,3‐a]quinoline ( 3 ). (6S)‐ 4 was coupled with Boc‐Gly, Boc‐L‐Asp(β‐benzyl ester), or Boc‐L‐Gln to give 6‐amino acid substituted (6S)‐3‐acetyl‐4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizines 5a , 5b , or 5c , respectively. After the removal of Boc from (6S)‐ 5a (6S)‐3‐acetyl‐6‐glycyl‐4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizine ( 6 ) was obtained. The anticancer activities of (6S)‐ 5 and (6S)‐ 6 in vitro were tested.     

Synthesis of enantiopure oxoindolo‐quinolizines

Methyl (1S,3S and 1R,3S)‐1‐(2, 2‐dimethoxyethyl)‐1,2,3,4‐tetrahydrocarboline‐3‐carboxylate ( 3 ) was hydrolyzed in the presence of sodium hydroxide to give (1S,3S and 1R,3S)‐1‐(2,2‐dimethoxyethyl)‐1,2,3,4‐tetrahydrocarboline‐3‐carboxylic acid ( 4 ), which was reduced with LiAlH₄ to provide (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐3‐hydroxymethyl‐1,2,3,4‐tetrahydrocarbolines ( 10 ), and then amidated in ammonia containing methanol to obtain (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐1,2,3,4‐tetrahydrocarboline‐3‐carboxamide ( 14 ). Acylation of (1S,3S and 1R,3S)‐ 3 , (1S,3S and 1R,3S)‐ 4 , (1S,3S)‐ 10 , (1R, 3S)‐ 10 , (1S, 3S)‐ 14 and (1R,3S)‐ 14 afforded the corresponding methyl (1S,3S and 1R,3S)‐1‐(2,2‐dimethoxyethyl)‐ 2‐(1,3‐dioxobutyl)‐1,2,3,4‐tetrahydrocarbolines‐3‐carboxylate ( 6 ), (1S,3S and 1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐1,2,3,4‐tetrahydrocarboline‐3‐carboxylic acid ( 5 ), (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐3‐(1,3‐dioxobutyl)oxymethyl‐1,2,3,4‐tetrahydrocarboline ( 11 ), (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐1,2,3,4‐tetrahydrocarboline‐3‐carboxamide ( 15 ), respectively. After Aldol reaction, dehydration and dehydrogenation the desired (6S)‐6‐substituted 4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizines 8 , 9 , 12 , 13 , and 16 were obtained. Their anticancer activities in vitro were investigated.     

Synthesis and Biological Evaluation of Pyrrolo[2,1‐f][1,2,4]triazine C‐Nucleosides with a Ribose, 2′‐Deoxyribose,and 2′,3′‐Dideoxyribose Sugar Moiety

The synthesis of hitherto unknown pyrrolo[2,1‐f][1,2,4]triazine C‐nucleosides is described. Structural variations (chlorine, bromine, iodine, and cyano groups) were introduced at position 7 of 4‐aza‐7,9‐dideazaadenine. In addition, pyrrolo[2,1‐f][1,2,4]triazine C‐nucleosides bearing a 2′‐deoxy‐, 2′,3′‐dideoxy‐, and 2′,3′‐dehydrodideoxyribose moiety were also prepared. Among these analogues, the pyrrolo[2,1‐f][1,2,4]triazine C‐ribonucleosides with either a hydrogen atom or cyano group at position 7 of the nucleobase displayed potent cytotoxic activity in a panel of various cancer cell lines.     

Synthesis and Evaluation of 1,1′‐Hydrocarbylenebis(indazol‐3‐ols) as Potential Antimalarial Drugs

Bis(indazol‐3‐ol) derivatives ( 5 , 30–38 ) were prepared by alkylation of 3‐alkoxyindazoles with α,ω‐dibromides, followed by removal of the O‐protecting groups. These compounds were subsequently evaluated as inhibitors of biocrystallization of ferriprotoporphyrin IX (heme) to hemozoin, a Plasmodium detoxification specific process. Most bis(5‐nitroindazol‐3‐ols) were good inhibitors, however, a denitro analogue ( 38 ), the intermediate bis(3‐alkoxyindazoles) ( 15 – 29 ) as well as bis(indazolin‐3‐ones) ( 39 – 42 ) were not active, showing the importance of the NO₂ and OH groups in the inhibition process.     

Synthesis and Structure–Activity Relationships of 1‐Benzyl‐4,5,6‐trimethoxyindoles as a Novel Class of Potent Antimitotic Agents

Combretastatin A‐4 derivatives : A series of combretastatin A‐4‐derived 1‐benzyl‐4,5,6‐trimethoxyindoles was designed and prepared as a novel class of potent antimitotic agents acting through the colchicine binding site on the microtubule.

     

6‐Aryl and Heterocycle Quinazoline Derivatives as Potent EGFR Inhibitors with Improved Activity toward Gefitinib‐Sensitive and ‐Resistant Tumor Cell Lines

A group of novel anilinoquinazoline derivatives with variable aryl and heterocyclic substituents at position 6 were synthesized and tested for their EGFR‐inhibitory activity. Aryl and heterocyclic rings were attached to the quinazoline scaffold through different linkages such as imine, amide, and thiourea. Most of the aryl and heterocyclic derivatives showed potent inhibition of wild‐type EGFR with IC₅₀ values in the low nanomolar range. Among these, thiourea derivatives 6 a , 6 b and compound 10 b also retained significant activity toward the gefitinib‐insensitive EGFR^T790M/L858R mutant, displaying up to 24‐fold greater potency than gefitinib. In addition, cell growth inhibitory activity was tested against cancer cell lines with wild‐type (KB cells) and mutant EGFR (H1975 cells). Several compounds including 6 a were found to be more potent than the reference compound gefitinib toward both cell lines, as was the case for compound 10 b against H1975 cells. Therefore, compounds 6 a and 10 b in particular may serve as new leads for the development of inhibitors effective against wild‐type EGFR as well as gefitinib‐resistant mutants.     

Synthesis and Structure of Highly Enantio‐ and Diastereoenriched 1‐Aza‐4‐oxa‐7‐thiabicyclo[3.3.0]octan‐8‐ones Derived from Acyl‐Substituted S‐Benzyl Thiocarbamates

A convenient method for the synthesis of the title compounds 4a,b, 3a,b via an intramolecular condensation of thiourethanes, derived from the acylation of enantioenriched α‐thio benzyllithium compounds, is reported. The structure of one of the major diastereomers was elucidated by a singlecrystal X‐ray analysis and compared to semiempirical calculations.     

Total Synthesis of (−)‐Doliculide,Structure–Activity Relationship Studies and Its Binding to F‐Actin

Actin, an abundant protein in most eukaryotic cells, is one of the targets in cancer research. Recently, a great deal of attention has been paid to the synthesis and function of actin‐targeting compounds and their use as effective molecular probes in chemical biology. In this study, we have developed an efficient synthesis of (?)‐doliculide, a very potent actin binder with a higher cell‐membrane permeability than phalloidin. Actin polymerization assays with (?)‐doliculide and two analogues on HeLa and BSC‐1 cells, together with a prediction of their binding mode to F‐actin by unbiased computational docking, show that doliculide stabilizes F‐actin in a similar way to jasplakinolide and chondramide C.     

Design and Synthesis of N‐Acylated Aza‐Goniothalamin Derivatives and Evaluation of Their in vitro and in vivo Antitumor Activity

Herein we describe the synthesis of a focused library of compounds based on the structure of goniothalamin ( 1 ) and the evaluation of the potential antitumor activity of the compounds. N‐Acylation of aza‐goniothalamin ( 2 ) restored the in vitro antiproliferative activity of this family of compounds. 1‐(E)‐But‐2‐enoyl‐6‐styryl‐5,6‐dihydropyridin‐2(1H)‐one ( 18 ) displayed enhanced antiproliferative activity. Both goniothalamin ( 1 ) and derivative 18 led to reactive oxygen species generation in PC‐3 cells, which was probably a signal for caspase‐dependent apoptosis. Treatment with derivative 18 promoted Annexin V/7‐aminoactinomycin D double staining, which indicated apoptosis, and also led to G₂/M cell‐cycle arrest. In vivo studies in Ehrlich ascitic and solid tumor models confirmed the antitumor activity of goniothalamin ( 1 ), without signs of toxicity. However, derivative 18 exhibited an unexpectedly lower in vivo antitumor activity, despite the treatments being administered at the same site of inoculation. Contrary to its in vitro profile, aza‐goniothalamin ( 2 ) inhibited Ehrlich tumor growth, both on the ascitic and solid forms. Our findings highlight the importance of in vivo studies in the search for new candidates for cancer treatment.     

Synthesis and Biological Evaluation of 10-Substituted Camptothecin Derivatives with Improved Water Solubility and Activity

Despite remarkable clinical achievements, camptothecin (CPT) still suffers from poor solubility and severe toxicity. Therefore, it is necessary to redevelop CPT derivatives as supplementary antitumor agents with good water solubility and small side effects. In this work, 27 camptothecin derivatives were synthesized and screened for their cytotoxicity against A549 (lung) and HCT-116 (colon) cancer cell lines. Among them, compound B7 , 7-ethyl-10-(2-oxo-2-(4-methylpiperidin-1-yl)ethoxy)camptothecin,was demonstrated in vitro to be a more potent antitumor agent than SN-38 by comparison of their inhibitory activities against cell proliferation and colony formation and interference effect on process of cell cycle and cell apoptosis. Additionally, a molecular docking model revealed that B7 can interact with the topoisomerase I–DNA complex, and that the solubility of B7 reached 5.73 μg/mL in water. Moreover, B7 significantly inhibited tumor growth in an A549 xenograft model at dosages of 0.4 and 2.0 mg/kg, and exhibited minimum lethal doses comparable to those of irinotecan. These results indicated that B7 , with improved solubility, enhanced activity and acceptable acute toxicity, can be used as a lead compound for the development of novel anticancer agents.     

Aza‐Henry Reaction of Isatin Ketimines with Methyl 4‐Nitrobutyrate en Route to Spiro[piperidine‐3,3′‐oxindoles]

A new enantioselective route to spiro[piperidine‐3,3′‐oxindoles] from isatin ketimines is described. The aza‐Henry reaction of N‐Boc‐isatin ketimines with methyl 4‐nitrobutyrate in the presence of a Ph₂BOX‐CuBr₂ complex provided the corresponding nitro amino esters with good diastereoselectivity and excellent enantioselectivity (up to >99% ee). The aza‐Henry adducts were transformed into spiro[piperidine‐3,3′‐oxindoles] after reduction of the nitro group to oxime, and cleavage of the N‐Boc group and lactamisation.

     

Cutting Short the Asymmetric Synthesis of the Ramatroban Precursor by Employing ω‐Transaminases

Starting from an adequate ketone precursor previous reports required three steps for the preparation of (R)‐2,3,4,9‐tetrahydro‐1H‐carbazol‐3‐amine, a key intermediate for the synthesis of the antiallergic drug ramatroban. A single biocatalytic step was sufficient to prepare the target amine with >97% ee (HPLC) via reductive amination of the corresponding ketone using an ω‐transaminase as biocatalyst. Since the ketone was barely soluble under the reaction conditions employed, it was provided as a solid and still the reaction went to completion within 4 h at 50 mM substrate concentration. Although 2‐propylamine is regarded as an ideal amine donor, it turned out to be detrimental for the specific ketone precursor leading to the formation of various side products. These could be avoided by using (R)‐1‐phenylethylamine as the best suited amine donor. An alternative work‐up was developed via freeze‐drying of the reaction mixture, enabling the isolation of the desired (R)‐amine in excellent yield (96%) and enantiopure form on a preparative scale (500 mg). No purification steps (e.g., column chromatography, crystallisation) were required.

     

Replacement of the 4′‐Hydroxy Group of Amodiaquine and Amopyroquine by Aromatic and Aliphatic Substituents: Synthesis and Antimalarial Activity

4′‐Substituted analogues of amodiaquine and amopyroquine were synthesized using Csp²–Csp² and Csp²–Csp³ Suzuki–Miyaura cross‐coupling reactions as the key step. The new derivatives were found to be active against both chloroquine (CQ)‐sensitive and CQ‐resistant strains of P. falciparum, with IC₅₀ values in the range of 7–200 nM ; one compound showed in vivo activity.

     

Synthesis and Biological Evaluation of Indole‐2‐carbohydrazide Derivatives as Anticancer Agents with Anti‐angiogenic and Antiproliferative Activities

A novel series of indole‐2‐carbohydrazide derivatives were synthesized, characterized, and evaluated for their antiproliferative activities against two cancer cell lines, HCT116 and SW480, and a normal human fetal lung fibroblast cell line, MRC‐5. Among this series, compound 24 f displayed potent cytotoxic activities in vitro against HCT116 and SW480 cell lines with GI₅₀ values of 8.1 and 7.9 μm , respectively, and was inactive against MRC‐5 cells. The newly synthesized compounds were also evaluated for anti‐angiogenesis capabilities by chick chorioallantoic membrane, human umbilical vein endothelial cell (HUVEC) migration, and endothelial microtubule formation assays. Moreover, the effects of 24 f on the vascular endothelial growth factor receptor‐2 and the signaling pathway in HUVECs indicated that this compound inhibits VEGFR‐2 and its downstream related proteins. These results indicate that compound 24 f , as well as the other derivatives, are promising inhibitors of angiogenesis.     

Asymmetric One‐Pot Synthesis of 1,4‐Dihydroquinolines via an Organocatalytic Aza‐Michael/Michael Cascade Strategy

A synthetic method for the construction of fully substituted enantioenriched 1,4‐dihydroquinolines using an organocatalytic aza‐Michael/Michael cascade reaction has been developed. The asymmetric reaction of 2‐(tosylamino)phenyl α,β‐unsaturated ketones with alkynyl aldehydes, promoted by diphenylprolinol O‐TMS ether as an organocatalyst, generated chiral 1,4‐dihydroquinolines in good to high yields with excellent enantioselectivities (up to 97 % ee).

     

Synthesis and Quantitative Structure–Activity Relationships of Selective BCRP Inhibitors

The breast cancer resistance protein (BCRP/ABCG2) is a member of the ABC transporter superfamily. This protein has a number of physiological functions, including protection of the human body from xenobiotics. The overexpression of BCRP in certain tumor cell lines causes cross‐resistance against various drugs used in chemotherapeutic treatment. In a previous work we showed that a new class of compounds derived from XR9576 (tariquidar) selectively inhibits BCRP. In this work we synthesized more members of this class, with modification on the second and third aromatic rings. The inhibitory activities against BCRP and P‐gp were assayed using a Hoechst 33342 assay for BCRP and a calcein AM assay for P‐gp. Finally, quantitative structure–activity relationships for both aromatic rings were established. The results obtained show the importance of the electron density on the third aromatic ring, influenced by substituents, pointing to interactions with aromatic residues of the protein binding site. In the second aromatic ring the activity of compounds is influenced by the steric volume of the substituents.     

Enantioselective Total Synthesis of (+)‐Gephyrotoxin 287C

Gephyrotoxin 287C, a bioactive alkaloid bearing a perhydropyrrolo[1,2‐a]quinoline skeleton with five stereocenters, is an attractive target for synthetic organic chemistry. We achieved an enantioselective total synthesis of (+)‐gephyrotoxin 287C, for which the key steps were palladium‐catalyzed asymmetric allylic amination using a chiral diaminophosphine oxide (DIAPHOX) preligand, diastereoselective intramolecular Mannich reaction, and tin tetrachloride‐catalyzed diastereoselective conjugate addition/protonation.