Natural products fragment-based design and synthesis of a novel pentacyclic ring system as potential MAPK Inhibitor

doi:10.21203/rs.3.rs-3396001/v1

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Natural products fragment-based design and synthesis of a novel pentacyclic ring system as potential MAPK Inhibitor

https://doi.org/10.21203/rs.3.rs-3396001/v1

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The synthesis of compounds based on fragments derived from natural products (NPs) serves as a source of inspiration for the design of pseudo-natural products (PNPs), to identify bioactive molecules that exhibit similar characteristics to NPs. These novel molecular scaffolds exhibit previously unexplored biological activities as well. This study reports the development and synthesis of a novel pentacyclic ring system, theindole-pyrimidine-quinoline (IPQ) scaffold. The design of this scaffoldwas based on the structural characteristics of four natural products, namelytryptanthrin, luotonin A, rutaecarpine, and camptothecin. Several successive steps accomplished the effective synthesis of the IPQ scaffold. The constituent componentsof the pentacycle, containingthe indole,quinazolinone, pyrimidone, and quinoline units, possess significant biological significance. Compound 1a demonstrated noteworthy anti-cancer efficacy against several human cancer cell lines among the tested compounds. The compound 1a was observed to elicit cell cycle arrest in both the G2/M and S phases, as well as trigger apoptosis in A549 cells. These effects were attributed to its ability to modulate the activation of mitochondrial-related mitogen-activated protein kinase (MAPK) signaling pathways.

Natural products (NPs) in drug development have been extensively investigated due to their significant contributions in terms of novel molecular scaffolds as well as potential biological properties [1–4]. However, the utilization of guided synthetic techniques for generating novel NP-inspired scaffolds is limited, resulting in a restricted range of accessible molecules. In recent times, the utilization of fragment-based drug discovery in the development of pseudo-natural products (PNPs) has gained significant attention. This method aims to amalgamate NP fragments, which are not associated with biosynthesis and possess diverse biological effects, to generate scaffolds that exhibit similarities to NPs but cannot be obtained through currently established biosynthetic pathways [5, 6].

The present research describes the design and synthesis of PNPs by integrating four distinct molecular fragments representing three separate classes of NPs, specifically quinazolinones, indoles, and quinolines. Polyheterocyclic systems, including quinazolinone and indole skeletons, have been identified as molecules of medical and pharmacological significance [7–10]. These compounds have demonstrated a diverse array of valuable biological activities, including anti-inflammatory, anti-hypertensive properties, and anti-cancer [11]. The indole-quinazolinone type alkaloids, namely Tryptanthrin (Tryp), luotonin A (luo A), and rutaecarpine (Rut), are represented in Fig. 1. Tryptanthrin, an indole-quinazoline alkaloid, was isolated from the Chinese medicinal plant Isatis einetoria and had significant anti-cancer and anti-inflammatory properties [12–17]. The compound luotonin A was extracted from the Chinese medicinal herb Peganum nigellastrum, and prior studies have shown its role as a topoisomerase I poison [18–21]. Rutaecarpine, a compound derived from the desiccated fruit of Evodia rutaecarpa, features numerous biological properties, including anti-thrombotic, antitumorigenic, and anti-inflammatory properties [22–24]. The quinoline ring serves as a structurally significant framework, frequently found in a wide range of NPs and pharmacological medicines [25]. The compound camptothecin (CPT), shown in Fig. 1, belongs to the class of quinoline alkaloids. It was initially isolated by Wall and Wani in 1966 from the plant Camptotheca acuminate. Camptothecin is an anti-cancer agent that selectively inhibits the activity of topoisomerase I, as evidenced by several studies [26–30].Given the substantial potential exhibited by Tryp, Rut, luo A, and CPT, this discussion focuses on a design methodology for synthesizing biologically significant small-molecule indole-pyrimidine-quinoline (IPQ) compounds. These compounds possess enhanced anti-cancer properties through modulating the MAPK signaling pathways.

Analogue-based pharmacophore design

To build novel scaffolds with noteworthy medicinal properties, the present research was centered on investigating the NPs that contain pharmacophores like quinazolinones, quinolines, and indoles. The significant biological importance of these pharmacophores has consistently captivated the interest of both synthetic and biological chemists, leading to substantial investigations into developing novel scaffolds and synthesizing new derivatives. Tryptanthrin and rutaecarpine are biologically active NPs that possess a pharmacophore consisting of quinazolinone and indole moieties. The quinolone scaffold serves as the pharmacophore for two widely recognized selective topoisomerase I inhibitors, namely camptothecin and luotonin A [31]. The IPQ was developed using the fragment-based compound synthesis, as shown in Fig. 1. The yellow highlighted region in Fig. 1 indicates the structural characteristic shared by pyrimidone was selected as the core template for four different NPs. The quinoline system, depicted in red in Fig. 1, was incorporated into the present design as the central framework, which was frequently found in camptothecin and luotonin A. The indole system (shown in purple in Fig. 1) was incorporated next to a pyrimidine moiety to construct a comprehensive pharmacophore with enhanced anti-tumor selectivity. The novel Tryp A-ring was substituted with quinoline, referred explicitly to as benzo-A-ring-aza-tryptanthrin. The structural composition of the novel five-membered ring closely resembled that of rutaecarpine since it encompassed both the pyrimidone and quinazolinone pharmacophores.

Chemistry

The synthesis of a novel pentacyclic molecule, including quinolone, quinazolinone, and indole moieties, is illustrated in Scheme 1. The synthetic methodology employed in this study entailed the condensation process of several isatin derivatives (6a-6d) with 2-aminoquinoline-3-carboxylate (4). The reaction may be regarded as an alteration of the conventional Niementowski reaction [32, 33]. A set of isatins (6a-6d) were synthesized in accordance with our prior research [34–36]. The initial step was the grinding reaction between 2-nitrobenzaldehyde (2) and ethyl cyanacetate, resulting in the formation of 2-cyano-3-(2-nitrophenyl)-ethyl acrylate (3). Compound 4 was prepared by reducing the subsequent nitro group of compound 3 using iron powder, followed by the hydrolysis of the ester. The reaction of compound 4 with thionyl chloride resulted in the formation of an essential intermediate, denoted as 4a. Ultimately, using the improved reaction conditions facilitated the conversion of the easily accessible isatins 6a-6d and 4a into compounds 1a-1d. The introduction of a substituent at the meta position of aniline has the potential to yield two distinct isatin products. The confirmation of this conclusion was based on the Beckmann rearrangement. The starting material, 5c, was utilized to produce two isomers, namely 5-fluoro-6-chloro isatin (6c') and 4-chloro-5-fluoro isatin (6c"). The ratio of 6c' to 6c" was determined to be roughly 1:1 by comparing the peak regions observed in the proton nuclear magnetic resonance (HNMR) spectra. At this juncture, the isolation of compounds 6c' and 6c" was not pursued further owing to their closely resembling polarities. Instead, these polarities were employed in the subsequent step to yield compounds 1c' and 1c" (Fig. 2). Compounds 1c' and 1c" were subjected to purification using high-performance liquid chromatography (HPLC) to facilitate the subsequent analysis of their molecular structures by ¹H NMR.

Antitumor Activity

Due to the novelty of the indole-pyrimidine-quinolone structure, it is plausible that this compound possesses anti-cancer properties that are now unknown or unexplored. Therefore, cancer cells were utilized to identify and differentiate bioactivities and ascertain molecular pathways. Using an in vitro assay, the activity of the derivatives was determined by performing cellular-based screening of all the compounds and controls (Gefitinib) on A549, HCT116, and MDA-MB-231 cell lines using the MTT cell viability assay. The IC₅₀ values acquired are shown in Fig. 3A. Compounds 1a-1d showed efficacy against A549, HCT116, and MDA-MB-231 cell lines. Specifically, compound 1a exhibited more favorable outcomes in inhibiting the growth of A549 and MDA-MB-231 cells compared to Gefitinib, as evidenced by IC₅₀ values of 0.34 and 3.54 µM, respectively. Compound 1c had notable efficacy in inhibiting the growth of cancer cells A549 and HCT116, as evidenced by its IC₅₀ values of 0.51 and 0.34 µM, respectively. Moreover, 1c' and 1c" underwent further purification and were subsequently assessed in vitro. The study's findings indicated that compound 1c' had superior activity against A549 cells, with IC₅₀ values of 0.43 µM, compared to compound 1c", which had IC₅₀ values of 0.53 µM. Furthermore, compounds 1b and 1d had limited efficacy on two cell lines, as evidenced by IC₅₀ values exceeding 10 µM. Given the favorable efficacy demonstrated by compound 1a on A549 cell lines, a subsequent assessment was conducted to examine the anti-tumor activity of compound 1a further.

In the initial step, compound 1a at concentrations ranging from 0 to 1.5 µM for durations of 24, 48, and 72 hours was added to A549 cells. Subsequently, the inhibitory rates of cell growth were assessed using the MTT test. According to the data presented in Fig. 3B, the cell viability decreased with increasing concentrations of 1a. Additionally, the rates of proliferation inhibition exhibited a progressive increase. At 24, 48, and 72 hours, the IC₅₀ values for A549 cells were 0.43, 0.34, and 0.25 µM, respectively.

Subsequently, the inhibition of cellular migration by compound 1a on A549 cells was assessed using the cell scratch test. As seen in Fig. 4, compound 1a at concentrations of 0, 0.11, 0.22, and 0.34 µM was given to A549 cells. The inhibition rates exhibited considerable differences at 0, 24, and 48 hours. Comparing the experimental group to the control group for the scratch assay, a statistical significance of p < 0.01 was observed. The inhibitory rates observed in the 24-hour groups were 22%, 31%, and 38%, whereas the inhibition rates in the 48-hour groups were 50%, 56%, and 60%, respectively. As the concentration of compounds increased, there was a corresponding enhancement in their anti-cancer action, resulting in higher rates of cancer cell inhibition. Hence, it can be shown that compound 1a effectively impedes the migration of A549 cells, with the observed effect displaying a concentration-dependent pattern.

After that, a flow cytometry analysis was conducted to determine whether compound 1a inhibited cell proliferation via cell cycle arrest. The A549 cells were subjected to treatment with varying concentrations of 1a (0, 0.11, 0.22, and 0.34 µM). The findings displayed in Fig. 5A indicated a significant difference in cell cycle arrest during the G2/M and S phases between the A549 cells and the control group. Subsequently, to ascertain the potential of compound 1a in inducing cellular apoptosis, A549 cells were subjected to treatment with several concentrations of 1a, as mentioned before, for 48 hours. Following this treatment, flow cytometry analysis assessed the percentage of cells undergoing apoptosis. According to the data presented in Fig. 5B, the overall proportion of apoptotic cells within the A549 cell population subjected to a treatment consisting of 0.34 µM of compound 1a was determined to be 27.29%. According to the results of this investigation, compound 1a can cause A549 cells to undergo apoptosis.

Next, the effect of compound 1a was evaluated on levels of expression of proteins associated with apoptosis (caspase-3, BAX, and BCL-2) in A549 cells. Figure 6 demonstrates that the anti-apoptotic BCL-2 protein was expressed at significantly reduced levels following treatment with compound 1a. In contrast, the levels of expression of caspase 3 and BAX increased. Therefore, it is suggested that compound 1a caused the activation and initiation of the subsequent caspase cascade, specifically involving caspase 3. The findings of this study indicate that the apoptosis of A549 cells, triggered by compound 1a, is linked to the mitochondrial pathway.

The impact of compound 1a was evaluated on the MAPK signaling pathway. This pathway has been well recognized for its significance in the process of apoptosis in cancer cells. Extracellular signal-regulated kinase (ERK), in particular, plays a vital part in controlling the proliferation and differentiation of cells. By contrast, apoptosis has been linked to the activation of p38 and c-Jun N-terminal kinase (JNK). According to the data in Fig. 7, the expression levels of proteins of the phosphorylated (p)-JNK/JNK and p-ERK/ERK exhibited a reduction. In contrast, the expression levels of proteins of p-p38/p38 increased. It is indicated from the results of this investigation that the initiation of apoptosis in A549 cells by compound 1a might potentially occur through the activation of the MAPK signaling pathway.

Over the last decade, there has been a pressing need to create innovative anti-cancer medicines due to the persistent rise in drug resistance. Recently, the development of PNPs from the NPs using the fragmentation approach has demonstrated considerable success in generating bioactive compounds that exhibit potential as candidate drugs for the targeted treatment of specific disorders. This work unveiled a newly identified IPQ pentacyclic ring structure, which revealed a biologically intriguing fused scaffold. The compound 1a showed remarkable anti-cancer activity against three distinct carcinoma cell lines of human origins, namely HCT116, A549, and MDA-MB-231. The respective IC₅₀ values for these cell lines were measured as 0.34 µM, 3.54 µM, and 25.22 µM. The experimental findings demonstrated that the observed effect resulted from cell growth inhibition, leading to cell cycle arrest, specifically in the G2/M and S phases, and the induction of apoptosis in A549 cells. These effects were mediated through the regulation of mitochondrial-related and MAPK signaling pathways. The present study elucidated the molecular mechanism by which compound 1a promotes apoptosis in cancer cells, specifically highlighting its potential as a promising therapeutic intervention against non-small cell lung cancer (NSCLC).

Analytical-grade chemicals were utilized in this research. A 200–300 mesh silica gel was utilized for column chromatography. The NMR experiments and spectra were conducted using BrükerAvance 400 or 500 instruments, and the calibration was performed by utilizing residual undeuterated solvent (internal reference). The coupling constants were given in hertz (Hz), whereas the chemical shifts were recorded in parts per million (ppm) units. High-resolution mass spectrometry (HRMS) analyses were conducted using an Agilent Technologies 6520B Accurate-Mass Quadrupole Time-of-Flight Liquid Chromatography/Mass Spectrometry (Q-TOF LC/MS) instrument. The reaction's progression was observed using thin-layer chromatography (TLC). The column chromatography experiment involved the utilization of silica gel (60–120 mesh size). The abbreviations employed to denote the multiplicities were as follows: "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, and "m" for multiplet.

General procedure for synthesis of 2-Cyano-3-2-nitrophenyl-ethyl acrylate (3) and 2-aminoquinoline-3-carboxylic acid (4) according to previous article [37].

General procedure for synthesis of compounds 1a-1d

Compound 4 (0.01 mol) in benzene (10 mL) was added thionyl chloride (0.05 mol) dropwise at 0 ℃. The reaction mixture was refluxed for 2 h and was then evaporated to dryness in vacuo. The crude sulfinamide anhydride obtained was dissolved in DCM (10 mL), followed by the addition of isatins 6a-6d (0.01 mol), Et₃N (0.05 mol). The reaction mixture was refluxed for 1 h and then cooled to room temperature with an ice bath. The precipitate was filtered and the residue was purified by flash-column chromatography on silica gel to provide 1a-1c as yellow soild.

Indolo[2,1-b] pyrimidine[4,5-b] quinolin-7,13-dione (1a)

Yellow solid, yield 51%. m.p. >300 ℃, IR (KBr):3055, 3031, 1729, 1678, 1586, 1459, 1356, 1305, 1213, 766,750cm^− 1;¹HNMR (500 MHz, DMSO-d₆) δ 9.51 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.21 (d, J = 8.6 Hz, 1H), 8.04 (t, J = 7.7 Hz, 1H), 7.93 (dd, J = 16.8, 7.8 Hz, 2H), 7.81 (t, J = 7.6 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H) ppm; ¹³CNMR (125 MHz, DMSO-d₆) δ 182.5, 158.3, 158.1, 154.8, 150.5, 148.3, 146.0, 139.2, 138.1, 133.6, 129.7, 129.0, 128.3, 127.0, 125.0, 122.2, 117.3, 116.8 ppm; HRMS (ESI) Calcd for C₁₈H₁₀N₃O₂[M + H]⁺300.0768, found 300.0761.

9-fluoroindolo[2,1-b]pyrimidine[4,5-b]quinolin-7,13-dione (1b)

Yellow solid, yield 45%.m.p. >300℃; IR (KBr): 3084, 3049, 1731, 1695, 1592, 1476, 1352, 1252, 1206, 875, 831, 764 cm^− 1; ¹HNMR (500 MHz, DMSO-d₆) δ 9.52 (s, 1H), 8.51 (dd, J = 8.8, 4.1 Hz, 1H), 8.40 (d, J = 8.2 Hz, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.05 (t, J = 7.7 Hz, 1H), 7.87 (dd, J = 7.0, 2.6 Hz, 1H), 7.85–7.74 (m, 2H) ppm; ¹³CNMR (125 MHz, DMSO-d₆) δ 181.6, 158.3, 154.6, 150.5, 142.3, 139.2, 133.6, 129.8, 129.1, 128.4, 127.0, 124.4, 124.2, 118.7, 118.6, 117.2, 111.9, 111.7 ppm; HRMS(ESI)calcd for C₁₈H₈FN₃NaO₂ [M + Na]⁺ : 340.0493, found 340.0490; HRMS(ESI)calcd for C₁₈H₉FN₃O₂ [M + H]⁺ : 318.0673, found 318.0662.

9-fluoro-10-chloroindolo[2,1-b]pyrimidine[4,5-b]quinolin-7,13-dione; (1c')

Yellow solid, yield 25%. m.p. >300℃; ¹H NMR (400 MHz, DMSO-d₆) δ 9.54 (s, 1H), 8.61 (d, J = 6.0 Hz, 1H), 8.49 (dd, J = 8.8, 3.8 Hz, 1H), 8.44–8.36 (m, 1H), 8.26–8.20 (m, 1H), 8.16 (d, J = 7.5 Hz, 1H), 8.10–8.03 (m, 1H), 7.95–7.91 (d, J = 8.0 Hz,, 1H), 7.89–7.78 (m, 1H) ppm. HRMS (ESI) calcd for C₁₈H₈ClFN₃O₂ [M + H]⁺:352.0284, found 352.0277.

8-chloro-9-fluoroindolo[2,1-b]pyrimidine[4,5-b]quinolin-7,13-dione (1c")

Yellow solid, yield 24%. m.p. >300℃; ¹H NMR (400 MHz, DMSO-d₆) δ 9.54 (s, 1H), 8.49 (dd, J = 8.8, 3.8 Hz, 1H), 8.41 (d, J = 7.9 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.06 (dd, J = 8.4, 6.7 Hz, 1H), 7.94 (t, J = 9.2 Hz, 1H), 7.83 (t, J = 7.5 Hz, 1H) ppm. HRMS (ESI) calcd for C₁₈H₈ClFN₃O₂ [M + H]⁺:352.0284, found 352.0284.

9-methoxyindolo[2,1-b]pyrimidine[4,5-b]quinolin-7,13-dione(1d)

Yellow solid, yield 35%. m.p. >300℃; ¹H NMR (400 MHz, DMSO-d₆) δ 9.47 (s, 1H), 8.41–8.36 (m, 2H), 8.20 (d, J = 8.5 Hz, 1H), 8.05–8.01 (m, 1H), 7.80 (ddd, J = 8.0, 6.7, 1.1 Hz, 1H), 7.49–7.43 (m, 2H), 3.89 (s, 3H) ppm;

8-chloro-9-methylindolo[2,1-b]pyrimidine[4,5-b]quinolin-7,13-dione(1d)

Yellow solid, yield 35%. m.p. >300℃; IR (KBr): 3068, 1729, 1674, 1596, 1452, 1343, 1293, 1046, 1000, 773, 688 764 cm^− 1; ¹HNMR (400 MHz, CDCl₃) δ 9.35 (s, 1H), 8.48 (d, J = 8.2 Hz, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.98 (t, J = 7.8 Hz, 1H), 7.76 (d, J = 7.3 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 2.50 (s, 3H) ppm. HRMS (ESI) calcd for C₁₉H₁₁ClN₃O₂[M + H]⁺: 348.0534, found 348.0531.

Cell culture. HCT116, A549, and MDA-MB-231 cells were cultured in RPMI-1640 medium with 10% fetal calf serum (Corning), 100 U/mL streptomycin, and 100 U/mL penicillin. The cells were placed in an incubator for 24 hours at 37°C in a humidified environment with 5% (v/v) CO₂.

Cell proliferation assay. A549, HCT116, and MDA-MB-231 cells at a concentration of 5×10⁷ cells/L were added to a 96-well plate and incubated for 24 hours. The synthesized compounds were subjected to incubation at six distinct concentrations (3.125, 6.25, 12.5, 25, 50, and 100 µmol/L) with the cells for 48 hours. Compounds demonstrating IC₅₀ values below 3.125 µmol/L underwent further testing at six additional concentrations (0.31, 0.63, 1.25, 2.5, 5, and 10 µmol/L) to acquire more precise IC₅₀ values. The control group was not treated with any compounds. To determine the IC₅₀, the culture media was aspirated, and the cells were subjected to a 4-hour incubation period in the presence of 5 µM MTT. Subsequently, the MTT solution was aspirated, and 200 µL of dimethyl sulfoxide (DMSO) was added to each well. The absorbance measurement at a wavelength of 490 nm was conducted using a Spectra Max 190 spectrophotometer for each well.

In vitro scratch assay. The A549 cells were added to a 6-well plate and placed for 24 hours until confluent in an incubator. The cells were subsequently treated as mentioned in previous literature [38].

Cell cycle analysis. Flow cytometry was employed to assess the progression of the cell cycle. Compound 1a was applied to the cells for 48 hours at different doses (0, 0.11, 0.22, and 0.34 µM). The cells were then rinsed with PBS before being fixed overnight at 20°C with absolute ethanol. The post-harvest treatment protocol employed in this study was consistent with the methodology described in the relevant research [38].

Apoptosis assay. The Annexin V/propidium iodide (PI) detection kit was utilized to identify the early and late stages of apoptosis located in the lower and top right corners of the flow dot plot, respectively. The manufacturer's instructions were followed when performing the experimental procedures. A549 cells were subjected to various doses (0, 0.11, 0.22, and 0.34 µM) of compound 1a for 48 hours. The post-harvest treatment protocol employed in this study was followed from a previous study [38].

Western blot analysis. Following treatment with compound 1a, the cells were collected and subjected to lysis using radioimmunoprecipitation (RIPA) lysis buffer containing phosphatase and protease inhibitors while maintaining a low temperature in an ice bath. The post-harvest treatment protocol employed in this study was consistent with the methodology described in the relevant research [38]. The study utilized primary antibodies, including BCL-2, BAX, cleaved caspase-3, ERK, phosphorylated p-ERK, JNK, p-JNK, p38, p-p38, and β-actin. The primary and secondary antibodies were diluted at 1:1000 and 1:5000, respectively.

Statistical analysis. The results presented are the mean ± standard deviation (SD) of a minimum of three separate experiments (n = 3). The statistical analysis was conducted using Statistical Package for the Social Sciences (SPSS) software version 22.0 and GraphPad Prism version 8.0. The statistical analysis involved using a one-way analysis of variance (ANOVA) and applying Bonferroni's post hoc test. A statistically significant difference was defined as p < 0.05.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

The present work was supported by the Program for the National Natural Science Foundation of China (82204235, 81703924, 81803951 and 81973687). The Key Research and Development Program of Shaanxi Province (2018ZDCXL-SF-01-02-02). Science and Technology Young Nova Program of Shaanxi Province (2019KJXX-025). The Youth Innovation Team of Shaanxi Universities (Shaanxi [2019]90). The Foundation of Education Department of Shaanxi Province Government (NO. 18JK0212, 22JP019). The third batch of young outstanding talents support program in Shaanxi universities (Shaanxi provincial education working committee of Chinese Communist Party [2019], No. 95).

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Scheme 1 is available in the Supplementary Files section

floatimage1.jpeg
Graphical Abstract
Scheme1.png
Scheme 1. Synthesis of indolo[2,1-b] pyrimidine[4,5-b]quinolin -7,13-dione
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Natural products fragment-based design and synthesis of a novel pentacyclic ring system as potential MAPK Inhibitor

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Abstract

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Introduction

Result and Discussion

Analogue-based pharmacophore design

Chemistry

Antitumor Activity

Conclusion

Experimental Sections

General procedure for synthesis of compounds 1a-1d

Indolo[2,1-b] pyrimidine[4,5-b] quinolin-7,13-dione (1a)

9-fluoroindolo[2,1-b]pyrimidine[4,5-b]quinolin-7,13-dione (1b)

9-fluoro-10-chloroindolo[2,1-b]pyrimidine[4,5-b]quinolin-7,13-dione; (1c')

8-chloro-9-fluoroindolo[2,1-b]pyrimidine[4,5-b]quinolin-7,13-dione (1c")

9-methoxyindolo[2,1-b]pyrimidine[4,5-b]quinolin-7,13-dione(1d)

8-chloro-9-methylindolo[2,1-b]pyrimidine[4,5-b]quinolin-7,13-dione(1d)

Declarations

References

Scheme 1

Supplementary Files

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