Design, Synthesis and Anticancer Activity Studies of Novel Indole Derivatives as Bcl-2/Mcl-1 dual inhibitors

doi:10.21203/rs.3.rs-2069030/v1

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Design, Synthesis and Anticancer Activity Studies of Novel Indole Derivatives as Bcl-2/Mcl-1 dual inhibitors

https://doi.org/10.21203/rs.3.rs-2069030/v1

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A series of novel indole derivatives were designed, synthesized and evaluated for the binding affinity of Bcl-2 family proteins and antiproliferative activity against three selected cancer cell lines (PC-3, Jurkat, and MDA-MB-231). The preliminary structure-activity relationship (SAR) for this indole scaffold was summarized. Among all the compounds, compound 9k showed the best inhibitory activity against Bcl-2 and Mcl-1 proteins with IC₅₀ values of 7.63 µM and 1.53 µM, respectively, which is comparable to the positive control AT-101. The docking study of it with Bcl-2 and Mcl-1 proteins indicated that it could bind to the active pocket of them through Van der Waals forces, hydrogen bond, etc. However, the three compounds with good binding affinity of Bcl-2 protein exhibited weaker antitumor activity compared to AT-101, which need further modification.

Indole

Bcl-2/Mcl-1

Antitumor

Inhibitory activity

Cancer is one of complex life-threatening diseases, which can appear in anywhere on the body, accounts for numbers of deaths each year, and threats to public health [1, 2]. The typical characteristic of cancer is the uncontrolled growth and spread of abnormal cells [3]. Cancer is a multifaceted and multi-mechanistic disease [4, 5]. Due to the fact that cancer is the second leading cause of death just after cardiovascular diseases, it is still a tricky health problem around the world [6, 7]. Nowadays, although there are significant progresses in the diagnostic techniques and management of cancer, it remains a great challenge for the successful treatment of cancers. In view that chemotherapy is one of the important means of cancer treatment, the development of newer and safer anticancer agents is of utmost importance [8].

Bicyclic heterocyclic structures is widely existed in various biologically important molecules, which could be isolated from natural products or obtained from organic synthesis [9, 10]. Since these structures contain at least one heteroatom, such as nitrogen, sulphur, and oxygen, and at least one carbon atom, they usually work as hydrogen bond acceptors and donors. Thus, they can bind to biological targets through hydrogen bonds effectively. In addition, they can improve the aqueous solubility of drug molecules to obtain the excellent pharmacotherapeutic properties [11]. Among these various bicyclic heterocyclic compounds, indole with versatile nature received considerable attention because of its potential as a privileged scaffold in drug development [12].

In recent years, several indole containing compounds have been shown to display versatile pharmacological activities. For instance, compound 1 showed high binding affinity for Bcl-2 family proteins, which are attractive targets for cancer therapy[13], compound 2 (Alocasin A) was an anti-fungal agent [14], Compound 3 (Panobinostat) is a marketed drug for treatment of multiple myeloma [15], compound 4 showed the potent inhibitory activity against HDACs and anti-proliferative activity against human acute monocytic leukemia cells [16], compound 5 (Indometacin) can be used in treatment of migraine and for headaches, compound 6 (pindolol) is used for the treatment of hypertension since 1982 [10] (Fig. 1). Considering indole-based agents showed broad and interesting biological activities, we attempt to design novel anticancer agents based on indole scaffold.

In our previous studies, a series of indole-based compounds were found to show Bcl-2 inhibitory activities [17]. Some of them showed potent inhibitory activities against Bcl-2 and Mcl-1 proteins, however, they showed poor antiproliferative activities. Therefore, these indole-based compounds were chosen for the further modification to discover novel antitumor agents. We tried to modify these compounds by simplifying their structures to obtain smaller molecules, which may easy to enter in tumor cells to exert their antitumor effects. Subsequently, two novel series of compounds (9a-9m and 10a-10m) were designed and synthesized (Fig. 2). Then, the relevant studies about bioactivity of them against Bcl-2 family proteins and some cancer cell lines were also completed and reported in this work.

Chemistry

The synthetic routes toward the target compounds are shown in Scheme 1. All the target compounds (9a-9m and 10a-10m) were synthesized in one step using commercially available Indometacin and a variety of amines in the presence of HATU (2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) and DIEA(diisopropylethylamine) by amide condensation reaction. Then, the target compounds were obtained in 6%~98% yields. All synthesized compounds were characterized by ¹H-NMR, ¹³C-NMR, HRMS and melting point analysis.

R₁ = 4-Cl-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 3-CH₃O-Ph-, 3-Br-Ph-, 3-F-Ph-, 3-CF₃-Ph-, 3-CHF₂-O-Ph-, 3-(CH₃CH₂)-Ph-, 2-thiazolyl-, 4-NO₂-Ph-, 3-NO₂-4-Cl-Ph-, Ph-; R₂ = 4-Br-Ph-, 4-CF₃-Ph-, 3,4-(Cl)₂-Ph-, 2-Cl-Ph-, Ph-, 4-Cl-Ph, 4-CH₃O-Ph-, 4-CH₃-Ph-, 3-Cl-Ph, 3-Cl-4-F-Ph-, 1-naphthyl-, 4-NO₂-Ph-, 2- Pyridyl-.

Scheme 1. Synthesis of the target compounds 9a-9m and 10a-10m

Reaction conditions: i) HATU, DIEA, DCM, rt.

Inhibitory activity against Bcl-2 family proteins

All the compounds were evaluated for their inhibitory activity against Bcl-2 protein at 50 µM against Bcl-2 using fluorescence-based method. In this assay, the Bcl-2 inhibitor AT-101 as the positive control drug. The results are summarized in Table 1. Among them, compounds 9k, 9m, and 10i showed better inhibition than others with inhibitory rates more than 60%. To further examine if the target compounds also show good inhibitory activities for other anti-apoptotic Bcl-2 proteins, these three compounds were chosen for further evaluation of inhibitory activity against Bcl-2 family proteins and the results are concluded in Table 2.

Table 1

Inhibition of all the target compounds against Bcl-2 protein at 5×10^− 5 mol/L
Cpd	R₁	R₂	Inhibition %	Cpd	R₁	R₂	Inhibition %
9a	3-NO₂-4-Cl-Ph-	-	4	10a	-	4-Br-Ph-	32
9b	4-NO₂-Ph-	-	7	10b	-	4-CF₃-Ph-	7
9c	Ph-	-	27	10c	-	3,4-(Cl)₂-Ph-	8
9d	4-Cl-Ph-	-	40	10d	-	2-Cl-Ph-	20
9e	3-Br-Ph-	-	26	10e	-	Ph-	7
9f	3-F-Ph-	-	5	10f	-	4-Cl-Ph	3
9g	CF₃-Ph-	-	4	10g	-	4-CH₃O-Ph-	52
9h	3-CHF₂-O-Ph-	-	3	10h	-	4-CH₃-Ph-	43
9i	3-(CH₃CH₂)-Ph-	-	25	10i	-	3-Cl-Ph	66
9j	2-thiazolyl-	-	27	10j	-	3-Cl-4-F-Ph-	7
9k	2-Cl-Ph-	-	82	10k	-	1-naphthyl-	31
9l	3-Cl-Ph-	-	16	10l	-	4-NO₂-Ph-	16
9m	3-CH₃O-Ph-	-	62	10m	-	2- Pyridyl-	33
AT-101	-	-	95

As the results (Table 2), compounds 9k, 9m and 10i exhibited potential inhibitory activities against Bcl-2 protein with IC₅₀ values of 7.63 µM, 29.6 µM and 34.3 µM, respectively. In addition, they showed good binding affinity of Mcl-1 protein with IC₅₀ values of 1.53 µM, 15.3 µM and 37.1 µM, respectively. Especially, compound 9k showed comparable activity against Bcl-2 with the positive control AT-101. Interestingly, these three compounds can selectively bind with Bcl-2 protein without interacting with Bcl-xL protein compared to AT-101. Generally, the electron withdrawing group of R₁ or R₂ (9k and 9c, 10i and 10e) is favor for the compounds’ inhibitory activity against Bcl-2 and Mcl-1 proteins.

Table 2

The binding affinities of representatives to three Bcl-2 family proteins.
Compound	IC₅₀ (µM)
Compound	Bcl-2	Mcl-1	Bcl-xL
9k	7.63 ± 2.91	1.53 ± 0.487	NA
9m	29.6 ± 13.3	15.3 ± 5.16	NA
10i	34.3 ± 10.3	37.1 ± 10.2	NA
AT-101	2.60 ± 1.11	1.19 ± 0.338	9.80 ± 0.61

Antitumor activity

To the best of our knowledge, Bcl-2 proteins is overexpressed in a variety of tumor cells, such as prostate, myeloma and acute leukemias. Thus, the cell viability assay was carried out to evaluate the effectiveness of the representatives with good binding affinity. Then, the compounds 9k, 9m and 10i were chosen for the evaluation of antitumor activity against three kinds of human cancer cell lines PC-3 (prostatic cancer cell), Jurkat (chronic myelogenous leukemia cell) and MDA-MB-231 (breast cancer cell) using CCK8 assay and the AT-101 as the positive control. The results are summarized in Table 3. Unfortunately, the results showed that all the compounds are inferior to the positive control AT-101. Among these three compounds, compound 10i exhibited the best anti-tumor activity against Jurkat cells with an IC₅₀ value of 39 µM, which need to be further modified. In general, our compounds displayed unideal cell viability, which need to be improved by modification.

Table 3 Antiproliferative activities of representative compounds.

Compound	IC₅₀(µM)
Compound	Jurkat	MDA-MB-231	PC-3
9k	69.0 ± 0.28	>100	>100
9m	>100	70 ± 5.4	>100
10i	39.0 ± 6.4	>100	>100
AT-101	3.12 ± 0.040	1.65 ± 0.020	12.0 ± 1.9

Molecular docking study of compound 9k

To further understand the possible interaction of compound 9k with Bcl-2 and Mcl-1 proteins, molecular simulation of compound 9k in Bcl-2 protein and Mcl-1 protein binding pocket was performed using Discover Studiuos2019R2 (Fig.3). In the docking study, the crystal structure of Bcl-2 (PDB code: 2O2F) and Mcl-1 (PDB code: 3WIX) were used. The results indicated that compound 9k could bind to the active pocket of Bcl-2 protein through Van der Waals forces, hydrogen bond, etc. The 4-chlorophenyl group of compound 9k could form one hydrogen bond with Gln96. In addition, there is pi-pi interaction between the 4-chlorophenyl group and Phe101(Fig. 3a-3b). For the binding of 9k with Mcl-1, 9k could stretch into the active pocket of Mcl-1 protein and there are interactions, such as Van der Waals forces and carbon hydrogen bond, between them(Fig. 3c-3d).

In conclusion, a series of novel indole derivatives as Bcl-2 inhibitors were designed and synthesized. The chemical structures of them were characterized by NMR and ESI-MS spectroscopic methods. The evaluation of these compounds against Bcl-2 and Mcl-1 proteins was carried out through TR-FRET assay and against Bcl-xL protein was carried out through FP assay. Among all the compounds, compound 9k showed the best inhibitory activity against Bcl-2 and Mcl-1 proteins with IC₅₀ values of 7.63 µM and 1.53 µM, respectively, which is comparable to AT-101. The preliminary SAR illustrated that the electron withdrawing group of R₁ or R₂ is favor for the inhibitory activity of the compounds against Bcl-2 protein. The docking study of 9k with Bcl-2 and Mcl-1 proteins showed that it could bind to the active pocket of them through Van der Waals forces, hydrogen bond, etc. The 4-chlorophenyl group of it could form one hydrogen bond with Gln96 of Bcl-2 protein. Subsequently, the compounds with good binding affinity were chosen for the evaluation of the antitumor activity using PC-3, Jurkat, and MDA-MB-231 cell lines by CCK method. It is regrettable that the three compounds showed poor antitumor activities compared to AT-101, which need further modification. In all, inhibitors 9k, 9m and 10i in this work might serve as bioactive fragments and hit compounds for developing more potent antitumor agents. The further modification of these compounds is ongoing in our lab.

General methods

In this work, all purchased materials were used directly without further purification. All reactions were detected on silica gel plates GF254 (Qingdao Haiyang Chemical, China) under UV light (365 nM or 254 nM). The purification of the products was carried out using column chromatography (silica gel 200–300 mesh). Melting points were determined on an X-5 micromelting apparatus and are uncorrected. The ¹H-NMR and ¹³C-NMR spectra of the products were recorded on a Bruker 400 MHz spectrometer. The analysis of spectrums was based on the solvent (2.5 ppm for ¹H- DMSO-d₆ or 7.26 ppm for ¹H-CDCl3). Coupling constants are expressed in Hz. The HRMS spectrums were conducted on an Agilent 6510 Quadrupole Time of-Flight LC/MS deliver.

Synthesis of compound 9a

To a round bottom flask were added Indomethacin 5 (0.36 g, 1 mmol) and 20 mL dichloromethane (DCM). When Indomethacin dissolved in DCM, N,N-Diisopropylethylamine (DIEA) (0.26 g, 2 mmol) was added and stirred for 10 min. Then, 2-(7-Azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hex- afluorophosphate (HATU) (0.46 g, 1.2 mmol) was added. The mixture was stirred at room temperature for 30 min. To this solution was added 3-nitro-4-chlorobenzenesulfonamide 7a (0.26 g, 1.1 mmol). The resulting solution was stirred at room temperature for 12 h. Upon completion of the reaction (monitored by TLC), the DCM was added, then organic layer was washed with 1 M citric acid solution and saturated sodium chloride solution, and then concentrated under vacuum. The residue was purified by silica gel chromatography to give the pure product 9a in 46% yield.

N-((4-chloro-3-nitrophenyl)sulfonyl)-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamide (9a)

White powder, yield: 46%. Mp: 174-176°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.83 (s, 1H), 8.54 (s, 1H), 8.16-8.18 (d, 1H, J = 8.0 Hz), 8.02-8.04 (d, 1H, J = 8.0 Hz), 7.65 (s, 4H), 6.87-6.89 (d, 2H, J = 8.0 Hz), 6.68-6.70 (d, 1H, J = 8.0 Hz), 3.70-3.73 (d, 5H, J = 12.0 Hz), 2.15 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.79, 168.28, 156.01, 141.40, 134.24, 131.77, 131.64, 129.53, 127.50, 126.68, 115.08, 112.67, 111.87, 101.86, 55.83, 31.59, 13.65. HRMS (ESI) calculated for C₂₅H₁₉Cl₂N₃O₇S([M - H]^-):575.0394, found 575.0315

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-((4-nitrophenyl)sulfonyl)acetamide (9b)

White powder, yield: 98%. Mp: 182-183°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.80 (s, 1H), 8.40-8.42 (d, 2H, J = 8.0 Hz), 8.16-8.18 (d, 2H, J = 8.0 Hz), 7.64 (s, 4H), 6.84-6.88 (m, 2H), 6.67-6.69 (m, 1H), 3.69-3.73 (d, 5H, J = 12.0 Hz), 2.15 (s, 3H).¹³C-NMR (100 MHz, DMSO-d₆) δ 169.87, 168.27, 155.95, 150.72, 144.77, 138.18, 136.30, 134.46, 131.63, 130.71, 129.71, 129.52, 124.89, 115.01, 112.45, 111.60, 102.13, 55.82, 31.70, 13.65. HRMS (ESI) calculated for C₂₅H₂₀ClN₃O₇S([M - H]^-):541.0783, found 541.0711.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-(phenylsulfonyl)acetamide (9c)

White powder, yield: 60%. Mp: 188-190°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.47 (s, 1H), 7.91-7.93 (d, 2H, J = 8.0 Hz), 7.60-7.63 (m, 7H), 6.86-6.93 (m, 2H), 6.67-6.70 (dd, 1H, J = 9.0 Hz, 2.0 Hz), 3.69-3.70(d, 5H, J = 4.0 Hz), 2.11(s, 3H).¹³C-NMR (100 MHz, DMSO-d₆) δ 169.48, 168.27, 156.02, 139.69, 138.14, 136.16, 134.51, 134.17, 131.62, 130.89, 130.61, 129.57, 129.43, 127.94, 115.04, 112.82, 111.87, 102.03, 55.87, 31.55, 13.62. HRMS (ESI) calculated for C₂₅H₂₁ClN₂O₅S ([M - H]^-):495.0787, found 495.0786.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-((4-chlorophenyl)sulfonyl)acetamide (9d)

White powder, yield: 42%. Mp: 171-173°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.57 (s, 1H), 7.92-7.94 (d, 2H, J = 8.0 Hz), 7.65-7.70 (m, 6H), 6.88-6.90 (m, 2H), 6.68-6.71 (m, 1H), 3.71 (s, 5H), 2.13 (s, 3H).¹³C-NMR (100 MHz, DMSO-d₆) δ 169.62, 168.27, 156.00, 139.20, 138.42, 138.17, 136.20, 134.50, 131.62, 130.85, 130.63, 130.00, 129.75, 129.52, 115.04, 112.69, 111.78, 102.03, 55.84, 31.60, 12.63. HRMS (ESI) calculated for C₂₅H₂₀Cl₂N₂O₅S([M - H]^-):529.0397, found 529.0395.

N-((3-bromophenyl)sulfonyl)-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamide (9e)

White powder, yield: 49%. Mp: 195-196°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.64 (s, 1H), 7.92-8.01 (m, 3H), 7.56-7.65 (m, 5H), 6.88-6.93 (m, 2H), 6.68-6.71 (dd, 1H, J = 9.0 Hz, 2.0 Hz), 3.72 (s, 5H), 2.14 (s, 3H).¹³C-NMR (100 MHz, DMSO-d₆) δ 169.76, 168.27, 156.04, 141.54, 138.16, 137.09, 136.22, 134.50, 131.93, 131.62, 130.84, 130.61, 130.26, 129.53, 127.01, 122.25, 115.07, 112.67, 111.88, 101.90, 55.86, 31.61, 13.64. HRMS (ESI) calculated for C₂₅H₂₀BrClN₂O₅S([M - H]^-):572.9892, found 572.9891.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-((3-fluorophenyl)sulfonyl)acetamide (9f)

White powder, yield: 59%. Mp: 182-183°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.60 (s, 1H), 7.75-7.77 (m, 1H), 7.57-7.68 (m, 7H), 6.85-6.90 (m, 2H), 6.65-6.68 (m, 1H), 3.69-3.70 (d, 5H, J = 4.0 Hz), 2.11 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.71, 168.27, 163.08, 160.61, 156.02, 141.62, 138.15, 136.23, 134.50, 132.06, 131.63, 130.84, 130.61, 129.52, 124.19, 121.36, 115.10, 115.06, 114.86, 112.68, 111.84, 101.93, 55.83, 31.60, 13.63. HRMS (ESI) calculated for C₂₅H₂₀ClFN₂O₅S ([M - H]^-):513.0692, found 513.0689.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-((3-(trifluoromethyl)phenyl)sulfonyl)acetamide (9g)

White powder, yield: 87%. Mp: 176-177°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.71 (s, 1H), 8.24-8.26 (d, 1H, J = 8.0 Hz), 8.12-8.16 (t, 2H, J = 8.0 Hz ), 7.87-7.91 (t, 1H, J = 8.0 Hz), 7.64 (s, 4H), 6.87-6.92 (m, 2H), 6.68-6.70 (m, 1H, J = 8.0 Hz), 3.70-3.73 (d, 5H, J = 12.0 Hz), 2.12 (s, 3H).¹³C-NMR (100 MHz, DMSO-d₆) δ 169.79, 168.28, 156.01, 138.14, 134.24, 131.78, 131.64, 130.58, 129.54, 127.49, 126.68, 115.08, 112.67, 110.87, 101.86, 55.83, 31.59, 12.65. HRMS (ESI) calculated for C₂₆H₂₀ClF₃N₂O₅S ([M - H]^-):563.0660, found 563.0659.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-((3-(difluoromethoxy)phenyl)sulfonyl)acetamide (9h)

White powder, yield: 51%. Mp: 108-110°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.51 (s, 1H), 7.97-7.99 (d, 2H, J = 8.0 Hz), 7.65 (s, 4H), 7.37-7.42 (t, 2H), 6.87-6.92 (m, 2H), 6.68-6.71 (m, 1H), 3.69-3.71 (d, 5H, J = 8.0 Hz), 2.14 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 171.51, 168.33, 156.06, 138.13, 135.89, 134.57, 131.65, 131.01, 130.66, 129.54, 115.09, 113.23, 111.86, 102.08, 55.87, 52.27, 29.59, 13.65. HRMS (ESI) calculated for C₂₆H₂₁ClF₂N₂O₆S ([M - H]^-):561.0704, found 561.0703.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-((3-ethylphenyl)sulfonyl)acetamide (9i)

White powder, yield: 56%. Mp: 175-176°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.41 (s, 1H), 7.82-7.84 (d, 2H, J = 8.0 Hz), 7.64 (s, 4H), 7.41-7.43 (d, 2H, J = 8.0 Hz), 6.88-6.94 (m, 2H), 6.68-6.71 (m, 1H), 3.68-3.71 (d, 5H, J = 12.0 Hz), 2.64-2.70 (m, 2H), 2.12 (s, 3H), 1.15-1.19 (t, 3H, J = 8.0 Hz). ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.43, 168.27, 156.01, 150.61, 138.15, 137.10, 136.13, 134.52, 131.61, 130.90, 130.61, 129.52, 128.84, 128.12, 115.03, 112.89, 111.83, 102.00, 55.84, 31.58, 28.50, 15.41, 13.64. HRMS (ESI) calculated for C₂₇H₂₅ClN₂O₅S([M - H]^-):523.1099, found 523.1097.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-(thiophen-2-ylsulfonyl)acetamide (9j)

White powder, yield: 90%. Mp: 217-219°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.58 (s, 1H), 7.99-8.01 (m, 1H), 7.75-7.76 (m,1H), 7.61-7.62 (m, 4H), 7.14-7.16 (t, 1H, J = 4.0 Hz), 6.92 (s, 1H), 6.85-6.87 (d, 1H, J = 8.0 Hz), 6.65-6.68 (m, 1H), 3.69 (s, 5H), 2.12 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.45, 168.29, 156.05, 139.92, 138.16, 136.20, 135.26, 134.78, 134.52, 131.63, 130.90, 130.64, 129.53, 127.96, 115.06, 112.79, 111.93, 101.97, 55.87, 31.61, 13.64. HRMS (ESI) calculated for C₂₃H₁₉ClN₂O₅S₂ ([M - H]^-):501.0351, found 501.0351.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-((2-chlorophenyl)sulfonyl)acetamide (9k)

White powder, yield: 86%. Mp: 174-177°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.89 (s, 1H), 8.07-8.09 (d, 1H, J = 8.0 Hz), 7.63-7.68 (m, 6H), 7.56-7.58 (m, 1H), 6.96-6.97 (d, 1H, J = 4.0 Hz), 6.87-6.89 (d, 1H, J = 8.0 Hz), 6.68-6.70 (m, 1H), 3.74-3.77 (d, 5H, J = 12.0 Hz), 2.16 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.49, 168.27, 156.01, 138.14, 136.67, 136.26, 135.72, 134.48, 132.74, 132.14, 131.63, 131.06, 130.88, 130.56, 129.52, 128.19, 115.06, 112.67, 112.01, 101.76, 55.84, 31.23, 13.66. HRMS (ESI) calculated for C₂₅H₂₀Cl₂N₂O₅S([M - H]^-):529.0397, found 529.0396.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-((3-chlorophenyl)sulfonyl)acetamide (9l)

White powder, yield: 66%. Mp: 192-195°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.62 (s, 1H), 7.86-7.87 (d, 2H, J = 4.0 Hz), 7.76-7.78 (d, 1H, J = 8.0 Hz), 7.62-7.64 (m, 5H), 6.85-6.90 (m, 2H), 6.65-6.68 (m, 1H), 3.69 (s, 5H), 2.11 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.79, 168.28, 156.01, 141.40, 138.14, 136.22, 134.49, 134.24, 134.05, 131.78, 131.64, 130.58, 129.54, 127.49, 126.68, 115.08, 112.67, 111.87, 101.86, 55.83, 31.59, 13.65. HRMS (ESI) calculated for C₂₅H₂₀Cl₂N₂O₅S([M - H]^-):529.0397, found 529.0393.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-((3-methoxyphenyl)sulfonyl)acetamide (9m)

White powder, yield: 54%. Mp: 153-155°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.46 (s, 1H), 7.64 (s, 4H), 7.50-7.52(m, 2H), 7.37 (s, 1H), 7.25-7.27 (d, 1H, J = 8.0 Hz), 6.87-6.94 (m, 2H), 6.68-6.70 (m, 1H), 3.78 (s, 3H), 3.70-3.71 (d, 5H, J = 4.0 Hz), 2.13 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.60, 168.28, 156.59, 156.00, 141.00, 138.13, 136.18, 134.51, 131.64, 130.88, 130.58, 129.53, 119.85, 119.80, 115.07, 112.89, 112.86, 111.85, 101.90, 56.05, 55.80, 31.63, 13.67. HRMS (ESI) calculated for C₂₆H₂₃ClN₂O₆S([M - H]^-):525.0892, found 525.0888.

The synthesis of 10a-10m is similar to 9a.

N-(4-bromophenyl)-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamide (10a)

Light yellow powder, yield: 49%. Mp: 184-186°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 7.64-7.71 (m, 4H), 7.58-7.60 (d, 2H, J = 8.0 Hz), 7.48-7.50 (d, 2H, J = 8.0 Hz), 7.17 (s, 1H), 6.92-6.94 (d, 1H, J = 8.0 Hz), 6.71-6.73 (d, 1H, J = 8.0 Hz), 3.74-3.76 (d, 5H, J = 8.0 Hz), 2.28 (s, 3H,). ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.16, 168.35, 156.03, 138.93, 138.09, 135.94, 134.64, 132.04, 131.64, 130.72, 129.54, 121.64, 114.35, 102.38, 55.90, 32.47, 13.88. HRMS (ESI) calculated for C₂₅H₂₀BrClN₂O₃([M - H]^-):509.0273, found 509.0271.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-(4-(trifluoromethyl)phenyl)acetamide (10b)

White powder, yield: 20%. Mp: 207-209°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.61 (s, 1H), 7.82-7.84 (d, 2H, J = 8.0 Hz), 7.65-7.71 (m, 6H), 7.17-7.18 (d, 1H, J = 4.0 Hz), 6.92-6.94 (d, 1H, J = 8.0 Hz), 6.71-6.74 (d, 1H, J = 8.0 Hz)，3.81 (s, 2H), 3.75 (s, 3H), 2.29 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.63, 168.35, 156.04, 138.09, 136.01, 134.64, 131.66, 130.71, 129.55, 126.57, 119.53, 114.20, 111.67, 102.35, 55.90, 32.50, 13.89. HRMS (ESI) calculated for C₂₆H₂₀ClF₃N₂O₃([M - H]^-): 499.1041, found 499.1041.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-(3,4-dichlorophenyl)acetamide (10c)

Yellow powder, yield: 16%. Mp: 184-185°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.52 (s, 1H), 8.01 (s, 1H), 7.67-7.71 (m, 4H), 7.57-7.59 (d,, 1H, J = 4.0 Hz), 7.50-7.52 (d, 1H, J = 8.0 Hz), 7.15 (s, 1H), 6.92-6.94 (d, 1H, J = 8.0 Hz), 6.71-6.74 (d, 1H, J = 12.0 Hz), 3.75-3.78 (d, 5H, J = 12.0 Hz), 2.27 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.51, 168.34, 156.04, 139.65, 138.10, 136.03, 134.62, 131.66, 131.46, 131.28, 131.20, 130.71, 129.55, 125.17, 120.83, 119.70, 115.09, 114.06, 111.67, 102.33, 55.91, 32.44, 13.88. HRMS (ESI) calculated for C₂₅H₁₉Cl₃N₂O₃([M - H]^-):499.0388, found 499.0388

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-(2-chlorophenyl)acetamide (10d)

White powder, yield: 10%. Mp: 151-152°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.70 (s, 1H), 7.64-7.71 (m, 5H), 7.49-7.51 (d, 1H, J = 8.0 Hz), 7.18-7.34 (m, 3H), 6.93-6.96 (d, 1H, J = 12.0 Hz), 6.71-6.74 (dd, 1H, J₁ = 4.0 Hz, J₂ = 8.0 Hz), 3.86 (s, 2H), 3.77 (s, 3H), 2.30 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.30, 168.35, 156.06, 138.09, 135.99, 135.29, 134.66, 131.67, 131.26, 130.75, 129.93, 129.53, 127.92, 126.91, 126.67, 115.08, 114.38, 111.90, 102.29, 55.90, 31.86, 13.89. HRMS (ESI) calculated for C₂₅H₂₀Cl₂N₂O₃([M - H]^-):465.0778, found 465.0777

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-phenylacetamide (10e)

Light green powder, yield: 65%. Mp: 165-166°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.24 (s, 1H), 7.59-7.71 (m, 6H), 7.28-7.32 (t, 2H, J = 8.0 Hz), 7.19-7.20 (d, 1H, J = 4.0 Hz), 7.03-7.06 (m, 1H), 6.92-6.94 (d, 1H, J = 8.0 Hz), 6.71-6.73(d, 1H, J = 8.0 Hz), 3.75 (s, 5H), 2.29 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 168.94, 168.35, 156.02, 139.60, 138.06, 135.87, 134.68, 131.65, 131.37, 130.72, 129.54, 129.22, 123.77, 119.68, 115.07, 114.60, 111.63, 102.42, 55.90, 32.49, 13.91. HRMS (ESI) calculated for C₂₅H₂₁ClN₂O₃([M - H]^-):431.1167, found 431.1164.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-(4-chlorophenyl)acetamide (10f)

White powder, yield: 14%. Mp: 189-190°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H), 7.63-7.71 (m, 6H), 7.35-7.38 (d, 2H, J = 12.0 Hz), 7.17-7.18 (d, 1H, J = 4.0 Hz), 6.92-6.94 (d, 1H, J = 8.0 Hz), 6.71-6.73 (d, 1H, J = 8.0 Hz), 3.76 (s, 5H), 2.27 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.11, 168.34, 156.03, 138.54, 138.08, 134.66, 131.66, 130.71, 129.54, 129.14, 121.22, 114.36, 110.66, 102.37, 55.90, 32.45, 13.90. HRMS (ESI) calculated for C₂₅H₂₀Cl₂N₂O₃([M - H]^-):465.0778, found 465.0775.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-(4-methoxyphenyl)acetamide (10g)

White powder, yield: 17%. Mp: 168-170°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.09 (s, 1H), 7.64-7.71 (m, 4H), 7.48-7.51 (m, 2H), 7.19 (s, 1H), 6.86-6.94 (m, 3H), 6.70-6.73 (dd, 1H, J₁ = 4.0 Hz, J₂ = 8.0 Hz), 3.75 (s, 3H), 3.71 (s, 5H), 2.28 (s, 3H).¹³C-NMR (100 MHz, DMSO-d₆) δ 168.43, 168.34, 156.02, 155.69, 138.05, 135.81, 134.69, 132.73, 131.65, 131.38, 130.73, 129.53, 121.28, 115.06, 114.72, 114.30, 111.62, 102.44, 55.89, 55.60, 32.39, 13.91. HRMS (ESI) calculated for C₂₆H₂₃ClN₂O₄ ([M - H]^-):461.1273, found 461.1273.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-(p-tolyl)acetamide (10h)

Yellow powder, yield: 60%. Mp: 163-164°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.15 (s, 1H), 7.64-7.71 (m, 4H), 7.47-7.49 (d, 2H, J = 8.0 Hz), 7.19 (s, 1H), 7.09-7.11 (d, 2H, J = 8.0 Hz), 6.92-6.94 (d, 1H, J = 8.0Hz), 6.70-6.73 (dd, 1H, J₁ = 4.0 Hz, J₂ = 8.0 Hz), 3.73-3.75 (d, 5H, J = 8.0 Hz), 2.28 (s, 3H), 2.24 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 168.69, 168.34, 156.01, 138.05, 137.09, 135.83, 134.69, 132.67, 131.65, 131.37, 130.72, 129.58, 129.53, 119.72, 115.06, 114.67, 111.62, 102.43, 55.89, 32.46, 20.91, 13.91. HRMS (ESI) calculated for C₂₆H₂₃ClN₂O₃([M - H]^-):445.1324, found 445.1323.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-(3-chlorophenyl)acetamide (10i)

White powder, yield: 21%. Mp: 190-191°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 7.83 (s, 1H), 7.64-7.71 (m, 4H), 7.45-7.48 (d, 1H, J = 12.0 Hz), 7.32-7.36 (t, 1H, J = 8.0 Hz), 7.10-7.17 (m, 2H), 6.92-6.94 (d, 1H, J = 8.0 Hz), 6.71-6.74 (d, 1H, J = 12.0 Hz), 3.75-3.77 (d, 5H, J = 8.0 Hz), 2.28 (s, 1H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.38, 168.34, 156.04, 141.01, 138.09, 135.98, 133.54, 131.66, 130.97, 129.55, 123.49, 119.11, 118.03, 103.36, 55.90, 32.47, 13.89. HRMS (ESI) calculated for C₂₅H₂₀Cl₂N₂O([M - H]^-):465.0778, found 465.0776.

N-(3-chloro-4-fluorophenyl)-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamide (10j)

White powder, yield: 8%. Mp: 192-194°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 7.93-7.95 (m, 1H), 7.65-7.71 (m. 4H), 7.48-7.50 (m, 1H), 7.36-7.41 (m, 1H), 7.16 (s, 1H), 6.92-6.94 (d, 1H, J = 8.0 Hz), 6.71-6.73 (d, 1H, J = 8.0 Hz), 3.75-3.76 (d, 5H, J = 4.0 Hz), 2.28 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.26, 168.34, 156.03, 138.10, 136.00, 134.63, 131.66, 131.29, 130.71, 129.55, 121.04, 114.16, 111.66, 102.33, 55.90, 32.37, 13.89. HRMS (ESI) calculated for C₂₅H₁₉Cl₂FN₂O₃([M - H]^-):483.0683, found 483.0683.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-(naphthalen-1-yl)acetamide (10k)

Light yellow powder, yield: 6%. Mp: 175-176°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.18 (s, 1H), 8.07-8.09 (m, 1H), 7.94-7.96 (m, 1H), 7.64-7.79 (m, 6H), 7.47-7.56 (m, 3H), 7.32-7.33 (d, 1H, J = 4.0 Hz), 6.95-6.98 (d, 1H, J = 12.0 Hz), 6.73-6.76 (dd, 1H, J₁ = 4.0 Hz, J₂ = 8.0 Hz), 3.94 (s, 2H), 3.79 (s, 3H), 2.35 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.72, 168.38, 156.10, 138.06, 134.16, 131.67, 129.53, 128.67, 126.54, 126.29, 126.05, 123.11, 122.50, 102.22, 55.91, 32.07, 13.99. HRMS (ESI) calculated for C₂₅H₂₀Cl₂N₂O([M - H]^-):481.1324, found 481.1323.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-(4-nitrophenyl)acetamide (10l)

White powder, yield: 14%. Mp: 190-191°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H), 8.22-8.25 (m, 2H), 7.85-7.89 (m, 2H), 7.65-7.71 (m, 4H), 7.17 (s, 1H), 6.91-6.94 (m, 1H), 6.71-6.74 (dd, 1H, J₁ = 4.0 Hz, J₂ = 8.0 Hz), 3.85 (s, 2H), 3.75-3.76 (d, 3H, J = 4.0 Hz), 2.29 (s, 3H).¹³C-NMR (100 MHz, DMSO-d₆) δ 169.99, 168.34, 156.05, 145.74, 142.66, 138.11, 131.67, 130.70, 129.55, 125.53, 119.32, 113.95, 111.70, 102.31, 55.90, 32.55, 13.90. HRMS (ESI) calculated for C₂₅H₂₀ClN₃O₅([M - H]^-):476.1018, found 476.1018.

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-(pyridin-2-yl)acetamide (10m)

Yellow powder, yield: 17%. Mp: 153-154°C. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.08 (s, 1H), 7.64-7.71 (m, 4H), 7.47-7.51 (m, 2H), 7.19-7.20 (d, 1H, J = 4.0 Hz), 6.84-6.94 (m, 3H), 6.70-6.73 (dd, 1H, J₁ = 4.0 Hz, J₂ = 8.0 Hz), 3.67-3.76 (m, 5H), 2.28 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.88, 168.35, 156.03, 152.47, 148.47, 138.68, 138.05, 135.99, 134.67, 131.65, 131.36, 130.71, 129.53, 119.96, 115.05, 114.41, 113.88, 111.62, 102.52, 55.89, 32.13, 13.92. HRMS (ESI) calculated for C₂₄H₂₀ClN₃O₃([M - H]^-):432.1120, found 432.1119.

Binding Assay for measuring the binding of Bcl-2 family proteins with the compounds

TR-FRET Assay

The assay was performed by TR-FRET technology using a peptide-ligand substrate and a recombinant Bcl-2 or Mcl-1 protein. The TR-FRET signal in the assay is related with the amount of ligand binding to Bcl-2. All of the binding reactions were carried out under room temperature. The 20 µl reaction mixture in buffer contains the indicated amount of the compound, Bcl-2 protein, ligand, and the reaction dyes. The reaction mixture were incubated for 120 min before reading the TR-FRET signal. For the background, ligand was replaced with assay buffer. Fluorescence signals for both the acceptor and donor dyes were measured on a Tecan Infinite M1000 plate reader. TR-FRET was recorded as the ratio of the fluorescence of the donor and the acceptor dyes.

FP Assay

The FP-based binding assay for Bcl-xL was carried out using Bcl-2 protein, 5-FAM-Bid-BH3 peptide and the compounds. The tested compounds and Bcl-xL protein were precultured in the assay buffer (1XPBS) for 30 min at room temperature. Then, 5-FAM-Bid-BH3 peptide was added and incubated for another 20 min.Under the condition of an excitation wavelength (485 nm) and an emission wavelength (535 nm), the polarization values were monitored by the Tecan GENios-Pro Injector Reader. In the binding experiments, the compounds were prepared in dimethylsulfoxide (DMSO) at seven concentrations (1 nM, 10 nM, 100 nM, 1 µM, 10 µM, 50 µM, 100 µM). The final concentrations of 5-FAM-Bid-BH3 peptide and Bcl-xLprotein were 10 nM and 125 nM, respectively. Finally, the IC₅₀ value of all compounds were calculated and obtained.

Cell viability assay

The antiproliferative activities of the representative target compounds and the positive control were measured by using the CCK8 (Cell Counting Kit8) assay. Briefly, the three tumor cells (PC-3, Jurkat, and MDA-MB-231) were cultured in DMEM or RPMI1640 medium with 10% FBS in humidified incubator (37°C, 5% CO₂). When the cells grow well, they were seeded in 96-well plates with a density of 4000-6000 cells per well and then incubated for 12 h. Subsequently, the indicated compounds with different concentrations were added and mixed with the growing cells. After indicated for 72 h, 15 µL CCK8 solution was added into each well and the plates were incubated for a further 4 h. The final optical density was monitored by a microtiter-plate reader at 450 nm.

Docking study

By using the Surflex-Dock program of Discover Studiuos2019R2, the molecular docking of 9k was performed. The Bcl-2 and Mcl-1 downloaded protein from PDB database is dewatered and hydrotreated, the chosen compound was optimized to the best dominant conformation, and other parameters were set at default values. Then, the docking was conducted. The Bcl-2 (PDB code: 2O2F) and Mcl-1 (PDB code: 3WIX) proteins were down loaded from the Protein Data Bank .

Acknowledgments

This work was supported by grants from National Natural Science Foundation of China (No.82104123), Natural Science Foundation of Shandong Province (No. ZR2020QH344), and the Project of Shandong Medical and Health Science and Technology (No. 2019WS393).

Compliance with ethical standards

Conflict of interest 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.

Zhang, S.; Chen, Y.; Tian, C.; He, Y.; Tian, Z.; Wan, Y.; Liu, T. Dual-target inhibitors based on BRD4: Novel therapeutic approaches for cancer. Curr Med Chem, 2021, 28(9), 1775-1795.
Dadashpour, S.; Emami, S. Indole in the target-based design of anticancer agents: A versatile scaffold with diverse mechanisms. Eur J Med Chem, 2018, 150, 9-29.
Zhang, Z.; Xing, X.; Guan, P.; Song, S.; You, G.; Xia, C.; Liu, T. Recent progress in agents targeting polo-like kinases: Promising therapeutic strategies. Eur J Med Chem, 2021, 217, 113314.
Kaushik, N.K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C.H.; Verma, A.K.; Choi, E.H. Biomedical importance of indoles. Molecules, 2013, 18(6), 6620-6662.
Wan, Y.; Fang, G.; Chen, H.; Deng, X.; Tang, Z. Sulfonamide derivatives as potential anti-cancer agents and their SARs elucidation. Eur J Med Chem, 2021, 226, 113837.
Taber, D.F.; Tirunahari, P.K. Indole synthesis: a review and proposed classification. Tetrahedron, 2011, 67(38), 7195-7210.
Liu, T.; Song, S.; Wang, X.; Hao, J. Small-molecule inhibitors of breast cancer-related targets: Potential therapeutic agents for breast cancer. Eur J Med Chem, 2021, 210, 112954.
Liu, T.; Wu, Z.; He, Y.; Xiao, Y.; Xia, C. Single and dual target inhibitors based on Bcl-2: Promising anti-tumor agents for cancer therapy. Eur J Med Chem, 2020, 201, 112446.
Wan, Y.; Li, Y.; Yan, C.; Yan, M.; Tang, Z. Indole: A privileged scaffold for the design of anti-cancer agents. Eur J Med Chem, 2019, 183, 111691.
Kumari, A.; Singh, R.K. Medicinal chemistry of indole derivatives: Current to future therapeutic prospectives. Bioorg Chem, 2019, 89, 103021.
Tantawy, M.A.; Nafie, M.S.; Elmegeed, G.A.; Ali, I.A.I. Auspicious role of the steroidal heterocyclic derivatives as a platform for anti-cancer drugs. Bioorg Chem, 2017, 73, 128-146.
de Sá Alves, F.R.; Barreiro, E.J.; Fraga, C.A. From nature to drug discovery: the indole scaffold as a 'privileged structure'. Mini Rev Med Chem, 2009, 9(7), 782-793.
Liu, T.; Wan, Y.; Liu, R.; Ma, L.; Li, M.; Fang, H. Design, synthesis and preliminary biological evaluation of indole-3-carboxylic acid-based skeleton of Bcl-2/Mcl-1 dual inhibitors. Bioorg Med Chem, 2017, 25(6), 1939-1948.
Kim, S.H.; Sperry, J. Synthesis of Alocasin A. J Nat Prod, 2015, 78(12), 3080-3082.
Atadja, P. Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett, 2009, 280(2), 233-241.
Liu, T.; Wan, Y.; Xiao, Y.; Xia, C.; Duan, G. Dual-target inhibitorsbBased on HDACs: Novel antitumor agents for cancer therapy. J Med Chem, 2020, 63(17), 8977-9002.
Xu, G.; Liu, T.; Zhou, Y.; Yang, X.; Fang, H. 1-Phenyl-1H-indole derivatives as a new class of Bcl-2/Mcl-1 dual inhibitors: Design, synthesis, and preliminary biological evaluation. Bioorg Med Chem, 2017, 25(20), 5548-5556.

Scheme1.png
Scheme 1. Synthesis of the target compounds 9a-9m and 10a-10m Reaction conditions: i) HATU, DIEA, DCM, rt.
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Design, Synthesis and Anticancer Activity Studies of Novel Indole Derivatives as Bcl-2/Mcl-1 dual inhibitors

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Chemistry

Inhibitory activity against Bcl-2 family proteins

Antitumor activity

Molecular docking study of compound 9k

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