Chromene Skeleton Research Articles

2,4-Diaryl-5H-chromeno [4,3-b]pyridines: Synthesis, Topoisomerase I and II Inhibitory Activity, and Cytotoxicity

Topoisomerase enzyme, since its discovery, has been a promising target for the discovery of anticancer agents. In our earlier study, we have designed and synthesized flexible 2,4,6-trisubstituted pyridine derivatives and studied their topoisomerase inhibitory activity and cytotoxicity against several human cancer cell lines. Further optimization of the flexible 2,4,6-trisubstituted pyridine derivatives led us to synthesize various rigid analogues. In continuation of the previously reported chromeno[4,3-b]pyridine derivatives, herein we have prepared eleven 2,4-diaryl-5H-chromeno[4,3-b]pyridine derivatives (Figure 1(b)). All compounds were evaluated for their topoisomerase I and II inhibitory activity and cytotoxicity against several human cancer cell lines. Prepared compounds contain rigid chromeno[4,3b]pyridine skeleton at one side of the central pyridine. Chromeno[4,3-b]pyridine and chromene skeleton were found to have a wide range of biological activities such as estrogen receptor β-selective ligand, TNF-α inhibition, and anti-inflammatory activity.

Lewis Acid‐Catalyzed Intramolecular [3+2] Cycloaddition of Cyclopropane 1,1‐Diesters with Alkynes for the Synthesis of Cyclopenta[c]chromene Skeletons

An efficient method to construct cyclopenta[c]chromene skeletons by Lewis acid-catalyzed intramolecular [3+2] cycloaddition of cyclopropane 1,1-diesters with alkynes is presented. Two new fused cycles can be formed in one step in moderate to excellent yields (up to 94 %), and the products can be converted into bioactive barbituric acid derivatives (1) under simple reaction conditions.

High-Pressure Access to the Δ9-cis- and Δ9-trans-Tetrahydrocannabinols Family

Diels-Alder reactions of a range of 1-(alkoxy/alkyl-substituted phenyl)buta-1,3-dienes with methyl vinyl ketone and methyl acrylate carried out in ethanol as the reaction medium under 9 kbar pressure were investigated. The use of high pressure as the activating method of the Diels-Alder reactions allows the efficient and endodiastereoselective generation of a series of cis-cyclohexenyl-benzene cycloadducts, which are selectively converted into their trans-epimers. The cis-cyclohexenyl-benzenes and trans-cyclohexenyl-benzenes produced are useful precursors for accessing substituted privileged cis-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene and trans-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene skeletons. The total syntheses of Δ(9)-cis-tetrahydrocannabinol (THC) and Δ(9)-trans-THC, through the use of selected Diels-Alder adducts, are described. Finally, a route for obtaining Δ(9)-trans-THC in both enantiomeric pure forms based on the (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP)-hydrazone method is also reported.

Expeditious Assembly of a 2‐Amino‐4H‐chromene Skeleton by Using an Enantioselective Mannich Intramolecular Ring Cyclization–Tautomerization Cascade Sequence

The concept of a “privileged medicinal scaffold” has emerged as one of the most guiding principles in the process of drug discovery. The privileged scaffold commonly consists of a rigid hetero-ring system that assigns a well-defined orientation of appended functionalities for target recognition. In the light of this, the accessibility of convenient methods for the diversification of privileged scaffold functionalities impacts on the success in seeking potential drugs. Undoubtedly, the discovery of novel synthetic methodologies to facilitate the preparation of compound libraries is a pivotal focal point in modern medicinal chemistry. Chromene, as one of the privileged scaffolds, often appears as an important structural component in both biologically active and natural compounds. It has widely appeared in natural alkaloids, tocopherols, flavonoids, and anthocyanins. Moreover, in recent years functionalized chromenes have played an ever-increasing role in the field of synthetic and medicinal chemistry. Among the diverse chromene systems, 2-amino-4H-chromenes are particularly privileged medicinal scaffolds for the generation of small-moleculebased ligands with highly pronounced spasmolytic, diuretic, anticoagulant, and antianaphylactic activities. In particular, the current interest in 2-amino-4H-chromene derivatives with a nitrile functionality arises from their potential application in the treatment of human inflammatory tumor necrosis factor (TNF)a-mediated diseases, such as rheumatoid and psoriatic arthritis. The corresponding cyano-functionalized benzopyranopyridine (inhibitor of MK-2) originating from the 2-amino-4Hchromene scaffold was found to inhibit mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK-2) and suppress the expression of TNFa in U937 cells. In the case of cancer therapy, the tumor antagonist HA14-1 and a family of related alkyl (4H-chromen-4-yl)cyanoacetates are a new class of small molecules that exhibit a binding activity for the surface pocket of the cancer-implicated Bcl-2 protein and induce apoptosis or programmed cell death in follicular lymphoma B cells and leukemia HL-60 cells. The 2amino-3-cyano-4H-chromene MX58151, with a 3-bromo-4,5dimethoxyphenyl substituent at the 4-position, represents a promising class of proapoptotic small-molecule agents with multiple action modes against the breast cancer cell line T47D, the lung cancer cell line H1299, and the colorectal cancer cell line DLD-1. It induces caspase-mediated apoptosis in tumor cells and is about as potent as or slightly more potent than the commonly prescribed anticancer alkaloids Vinblastine and Paclitaxel in the caspase activation assay. Furthermore, compound MX58151 might have an advantage for the treatment of the drug-resistant cancers as it retains activity in tumor cells resistant towards current antimitotic agents, taxanes (including Taxol and Taxotere), and the Vinca alkaloids. The inhibition of tubuline polymerization and disruption of preformed endothelial cell capillary tubules constitute other significant activities of 2-amino-3cyano-4-aryl-4H-chromenes of type 3 that can place them in the row of effective anticancer therapeutics with an analogous mode of action. Most recently, another 2-amino-4aryl-4H-chromene compound (IRSP inhibitor) has been discovered as an insulin-regulated aminopeptidase inhibitor. In particular, this inhibitor is maybe useful in therapeutic application including enhancing memory and learning functions. In view of the significance of this framework, efficient syntheses of 2-amino-4H-chromenes are of great interest. [a] Q. Ren, W.-Y. Siau, Prof. Dr. J. Wang Department of Chemistry, National University of Singapore 3 Science Drive 3, Singapore 117543 Fax: (+65)6516-1691 E-mail : chmwangj@nus.edu.sg [b] Prof. Dr. Z. Du, Prof. Dr. K. Zhang Faculty of Engineering and Light Industry Guang Dong University of Technology Guang Dong, 510006 (P.R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201100927.

High-Pressure Diels−Alder Cycloadditions between Benzylideneacetones and 1,3-Butadienes: Application to the Synthesis of (R,R)-(−)- and (S,S)-(+)-Δ8-Tetrahydrocannabinol

High-pressure Diels-Alder reactions of various alkoxy/alkyl-substituted benzylideneacetones with methyl-1,3-butadienes are reported. Activation by high pressure (8-11 kbar) in combination with the mild Lewis acid HfCl(4).2THF allows these reactions to efficiently and regioselectively produce a series of ortho-substituted cyclohexenyl-benzene cycloadducts, that are useful precursors for the expeditious construction of the privileged 6,6-dimethyltetrahydro-6H-benzo[c]chromene skeleton. Application to the synthesis of Delta(8)-trans-THC in both enantiomeric pure forms is based on the successful resolution of selected cycloadduct by the SAMP-hydrazone method.

Convenient synthesis and unusual reactivity of 2-oxo-2 H,5 H-pyrano[3,2- c]chromenes

The reaction of 4-oxo-4 H-chromen-3-carbaldehydes with coumarin-4-acetic acids under the Perkin conditions follows an interesting pathway that involves aldol reaction and subsequent intramolecular lactonization to afford 2-oxo-2 H,5 H-pyrano[3,2- c]chromene skeleton. In contrast to chromone-3-carbaldehydes, the same reaction with chromone-2-carbaldehydes yielded only the aldol condensation product. The reaction was performed under thermal and microwave conditions. The reactivity of 2-oxo-2 H,5 H-pyrano[3,2- c]chromenes in water, alcohol and acetic acid was described.

New Metal‐Catalyzed Synthesis of Quinoline and Chromene Skeletons.

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New Metal‐Catalyzed Synthesis of Quinoline and Chromene Skeletons

AbstractAlkoxy‐functionalized butadienylboronic esters have been synthesized starting from α,β‐unsaturated acetals and cross‐coupled with both N‐protected and N‐unprotected 2‐bromo‐ and 2‐iodoaniline, and with 2‐iodophenol. In particular, N‐tosyl‐protected dienylanilines can be transformed under mild conditions into quinolines and quinolinones, in the presence of a PdII catalyst. Moreover, the cross‐coupling reaction between butadienylboronic esters and iodophenol directly affords chromenes that can be successively transformed into chromenones. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

A synthetic study on antiviral and antioxidative chromene derivative.

An efficient synthesis of the antiviral and antioxidative chromene (1) was achieved. A small amount of chromene 1 could be derived from plastoquinones 2 and 3, the major constituents of the brown alga, Sargassum micracanthum. By the following synthetic scheme involving its application, many kinds of analogs can be synthesized for evaluation of their biological activity and mechanistic study. The total synthesis of 1, started from geranyl acetate and protected 2-bromo-6-methylhydroquinone, was executed with Sharpless asymmetric dihydroxylation for introduction of the terminal diol system and base-catalyzed sigmatropic rearrangement for construction of the chromene skeleton as the crucial steps. The stereochemistry at C-11' was reconfirmed by this synthesis.

Traceless Solid-Phase Synthesis of Cyclopenta[c]quinolines and Cyclopenta[c]chromenes via Hetero [6+3] Cycloadditions of Fulvene. A Facile Approach to the 11-Heterosteroids Framework

The hetero [6+3] cycloaddition of fulvenes to benzoquinones and iodoanilines provides an efficient route to the synthesis of cyclopenta[c]-4H-chromen-8-ol, benzo[d]cyclopenta[e]-3H-3-azin-8-ol and other 11-hetero steroids. The structure of the cyclopenta[c]chromene skeleton was confirmed by the X-ray structure analysis of thep-bromobenzoate of 39. A small library consisting of 110 examples was prepared by reacting benzoquinones or iodoanilines with resin 17.

Intramolecular Dehydro Diels—Alder Reactions of Diarylacetylenes: Synthesis of 5H‐Benzo[j]phenanthridine and 6H‐Naphtho[2,3‐c]chromene Skeletons.

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Intramolecular Dehydro Diels-AlderReactions of Diarylacetylenes: Synthesis of 5H-Benzo[j]phenanthridine and 6H-Naphtho[2,3-c]chromeneSkeletons

Intramolecular dehydro Diels-Alder reactions of aniline and phenol diarylacetylene derivatives lead to the formation of 5H-benzo[j]phenanthridine and 6H-naphtho[2,3-c]chromene skeletons.