Traditional medicines have contributed greatly over the centuries to the discovery and development of new therapeutic agents and indoloquinoline alkaloids may represent a new class of drug leads. Cryptolepine (5-methyl-5Hindolo[3,2-b]quinoline), neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline), isocryptolepine (5-methyl-5H-indolo[3,2-c]quinoline, extracted from the African medicinal plant Cryptolepis sanguinolenta, and isoneocryptolepine (5-methyl-5Hindolo[2,3-c]quinoline), which has never been found in nature, are isomeric tetracyclic compounds of particular interest due to their broad spectrum of biological activities including antiparasitic, antifungal, antibacterial, cytotoxic, anti-inflammatory and antihyperglycaemic. As a result, in the last 30 years hundreds of indoloquinoline analogues were synthesized and their biological activities evaluated. In this paper, we present an overview of the potential of indoloquinolines as scaffolds in drug discovery by reviewing the in vitro and in vivo biological activities of natural and synthetic analogues, as well as the proposed mechanisms of action and structure-activity relationships.

Indoloquinolines as Scaffolds for Drug Discovery

Carbolines and tetrahydrocarbolines are common structural motifs in pharmaceuticals and natural products.[1] β-Carboline and its saturated analog, tryptoline, are particularly prevalent[2,3] and continue to inspire methods to efficiently access them.[4,5] In contrast, methods to access the δ-[6] or α-isomer[7] are uncommon despite the important biological properties exhibited by these carbolines. In addition to antibacterial and antiplasmodial activities,[8] δ-carbolines are potential cancer therapeutics (SYUIQ-5),[9] and the α-carboline mescengricin was reported to be a potential neural protective agent (Figure 1).[10] We anticipated that each structural isomer of the carboline scaffold would be readily accessible from an appropriately ortho-substituted aryl azide through a C–H bond amination reaction if a transition metal catalyst was found that could unlock and control the reactivity embedded in the azide.



Figure 1

Selected examples of biologically active carbolines.



We recently reported that ruthenium trichloride-hydrate selectively transformed aryl azides into γ-carbolinium ions.[11] Extension of these conditions to the synthesis of the other carboline isomers, however, was not successful. Because of the paucity of methods to access δ-carbolines,[6] we decided to find the optimal conditions for their construction. After testing a variety of metal complexes,[12] we found that RhII2-carboxylates were unique in their ability to catalyze the conversion of aryl azide 1 into 2,[13] and the highest yield was attained using 5 mol% of [Rh2(esp)2] complex in dichloroethane [Eq. (1)].[14] Deprotonation of the δ-carbolinium ion using aqueous Na2CO3 produced 3,[15] which was easily purified using silica gel chromatography.




(1)


The scope and limitations of δ-carbolinium ion generation was examined by exposing a series of aryl azides 1 to the optimal reaction conditions. The azides for our study were synthesized in three steps from commercial 2-bromoanilines through a Suzuki cross coupling–azidation–methylation sequence.[16] We found that our amination reaction tolerated a range of substituents on the aryl azide portion of the substrate: azides bearing alkyl- and trifluoromethyl groups as well as halides were efficiently converted into δ-carbolinium ions (Table 1). The reaction was even tolerant of substitution adjacent to the azide (entry 8). While a range of groups was tolerated on the azide portion of the substrate, the reaction yield was severely attenuated if any additional substituents were added to the pyridinium ion moiety.



Table 1

Scope of RhII2-catalyzed δ-carboline formation.



With the successful synthesis of 1-methyl-δ-carbolinium triflates 2, the conversion of aryl azides bearing 4-substituted pyridinium ion ortho-substituents into β-carbolinium ions (5) was next attempted. To our delight, the rhodium(II)-catalyzed C–H bond amination conditions proved amenable to the synthesis of 5 from aryl azides 4 (Table 2). Subsequent reduction of the β-carbolinium ion with NaBH4 produced tryptoline 6, which was easily purified using silica gel column chromatography. The alkyl group on the pyridine nitrogen atom could be varied without attenuating the yield of the process as long as a stoichiometric amount of AgOTf was added (entries 2 and 3). The steric environment around azide could be increased through substitution without preventing product formation (entry 4). The electronic nature of the aryl azide could also be modulated without adversely affecting the reaction (entries 6–10): both electron donating- and electron-withdrawing groups were tolerated in the method. Importantly, meta-substituents could be appended to the aryl azide without compromising the yield of the reaction (entries 9 and 10). The resulting tryptolines 6i and 6j cannot be formed selectively from a Fischer indole synthesis.[17]



Table 2

Scope of RhII2-catalyzed tryptoline formation.



To illustrate the synthetic utility of this RhII2-catalyzed C–H bond amination method, (±)-horsfiline[18,19] was synthesized (Scheme 1). The aryl azide substrate (4k) for our amination reaction was synthesized in three steps (Suzuki-, azidation-, and methylation reactions, 67%) from commercially available 2-bromo-4-methoxyaniline and 4-pyridinylboronic acid. Exposure of azide 4k to our amination-reduction sequence produced tryptoline 6k in 91%. Oxidation of 6k using N-bromosuccinimide[20] in aqueous acetic acid afforded (±)-horsfiline.[21] Using the same oxidative conditions, tryptoline 6g was converted into spirocyclic oxindole 7 in 71 %. Our overall yield for (±)-horsfiline and 7 for the six steps from the 2-bromo-4-substituted-anilines was 53 % and 42 %, respectively.



Scheme 1

Synthesis of (±)-horsfiline and analog.



Finally, aryl azides with meta-substituted pyridinium ion ortho-substituents were examined as potential substrates [Eq. (2)]. In contrast to azides 1 or 4, this class of substrates contains two C–H bonds that potentially could be transformed into C–N bonds. Using RuCl3H2O as the catalyst, the reaction occurred solely at C–Hb to produce γ-carbolinium ion 9 as the only product.[11] In contrast, exposure of 8 to [Rh2(esp)2] resulted in the formation of the α-isomer as the only product.[22] We are actively investigating the mechanistic implications of this turnover in selectivity.




(2)


To further investigate this selectivity trend, a series of meta-substituted pyridinium ions were submitted to reaction conditions (Table 3). Basification of the reaction mixture using Na2CO3 produced 11, which was purified using silica gel chromatography. Similar to the other isomers, construction of the α-isomer tolerated both electron-donating and electron-withdrawing aryl azide substituents (entries 1–7) although the yield was diminished in the presence of a para-methoxy group (8b, entry 2). An expanded scope of α-isomer formation was observed: substitution on the pyridinium ion portion of 8 was tolerated to allow access to 11h and 11i (entries 8 and 9).



Table 3

Scope of RhII2-catalyzed α-carboline formation.



Because our reaction tolerated substitution on the pyridinium moiety, we anticipated that our method might facilitate access to neocryptolepine.[23,24] This indoloquinoline alkaloid exhibits promising cytotoxicity toward cancer cells as well as strong antiplasmodial activity toward chloroquinine-resistant strains.[24f,25] Exposure of azide 8j to [Rh2(esp)2] resulted in amination of only the C–Ha bond to produce neocryptolepine (11j) as a single regioisomer in 68% (entry 10).

In conclusion, we have developed a method to access α-, β-, or δ-carbolinium ions from aryl azides with ortho-pyridinium ion substituents using 1–5 mol% of [Rh2(esp)2]. In combination with our previous report using RuCl3 to access γ-carbolinium ions, we believe our work demonstrates that metal-catalyzed C–H bond amination is a simple, efficient strategy to access all possible carbolinium ion isomers from readily accessible aryl azides. The synthetic utility of our method was illustrated in a four-flask synthesis of cytotoxic and antiplasmodial agent, neocryptolepine and the analgesic oxindole (±)-horsfiline. By synthesizing a chlorinated analog of horsfiline—one not readily accessible through previously reported syntheses—we demonstrated that the modular nature of our method facilitates the construction of natural and non-natural alkaloids.

/pdf/rh-ii-2-catalyzed-synthesis-of-a-b-or-d-carbolines-from-aryl-2f11g00pap.pdf

Rh II 2 -catalyzed synthesis of α-, β-, or δ-carbolines from aryl azides

A new approach to the synthesis of benzofuro[3,2-b]quinolines, benzothieno[3,2-b]quinolines and indolo[3,2-b]quinolines†

Discovery of novel, potent, selective and cellular active ADC type PTP1B inhibitors via fragment-docking-oriented de novel design

The discovery of novel, potent ERR-alpha inverse agonists for the treatment of triple negative breast cancer.

Synthesis and Antitumor Activity of Fused Quinoline Derivatives. Part 4. Novel 11‐Aminoindolo(3,2‐b)quinolines.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

K. Harada

Author Tools

Chat about Author

Papers

Synthesis and Antitumor Activity of Fused Quinoline Derivatives. Part 4. Novel 11‐Aminoindolo(3,2‐b)quinolines.