Strong In Vitro And Vivo Cytotoxicity Of Two Platinum(II) Complexes With Cryptolepine Derivatives

doi:10.21203/rs.3.rs-286247/v1

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Strong In Vitro And Vivo Cytotoxicity Of Two Platinum(II) Complexes With Cryptolepine Derivatives

https://doi.org/10.21203/rs.3.rs-286247/v1

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Two mononuclear Pt(II) compounds, [Pt(BQL1)Cl]Cl (BQL1-Pt) and [Pt(BQL2)Cl]Cl (BQL2-Pt) with [5-(benzo[4,5]furo[3,2-b]quinolin-11-yloxy)-pentyl]-bis-pyridin-2-ylmethyl-amine (BQL1) and [9-(benzo[4,5]furo[3,2-b]quinolin-11-yloxy)-nonyl]-bis-pyridin-2-ylmethyl-amine (BQL2), were prepared as new chemotypes for potential antitumor agents. This study evaluated the influence of cryptolepine derivatives in BQL1-Pt, 2,2′-dipicolylamine Pt(II) complex, and BQL2-Pt on cellular Pt(II) accumulation, cytotoxicity, and in vitro and in vivo antitumor activities against T-24 cancer cells and normal HL-7702 cells. BQL1-Pt and BQL2-Pt displayed cytotoxic activities in the micromole range (1.3±0.1 and 0.2±0.2 μM, respectively) on T-24 cancer cells; however, they did not exhibit any toxicity against HL-7702 cells. They triggered T-24 cell apoptosis through a mitochondrial dysfunction pathway. Compared to 2,2′-dipicolylamine, the neutral BQL1 and BQL2 ligands with cryptolepine derivatives increased the planarity and branched chain resulting in BQL1-Pt and BQL2-Pt with favorable antitumor activities. Further, BQL2-Pt effectively inhibited the growth of bladder T-24 tumor in vivo. BQL2-Pt can act as a potential therapeutic candidate for cancer treatment.

General Biochemistry

cryptolepine derivatives Pt(II) complex

antiproliferative activity

mitochondria damage

Among transition metal complexes, cisplatin-based compounds have emerged as ubiquitous antitumor agents [1 − 10]. However, cisplatin-based drugs have several disadvantages, such as high toxicity, drug tolerance, and adverse drug reaction [10 − 19]. These disadvantages have fostered the search for antiproliferative Pt-based compounds with more effective outcomes and fewer side effects [20–30], such as 1-methyl-7-azaindole (L) cis- and trans-isomers of [PtCl₂(L)(NH₃)] compounds [20], [1,2-diamino-1-(4-fluorophenyl)alkanol]-dichloridoplatinum(II) analogs [21], glycosylated Pt(IV) complexes [22], pyrazine (pz) Pt(II) complexes [23], bimetallic [(NHC)PtX₂]₂(diamine) complexes [24] and terpyridine binuclear Pt^II complexes [25–27]. In particular, many researchers, including us, have focused on metal coordination compounds/complexes including traditional Chinese medicine (TCM) components [31 − 40]. Previously reported that TCMs metal complexes possesses high anticancer activity and selectivity, and thus most of them have been extensively considered as an ideal anticancer drugs and G4 DNA ligands [31 − 54]. Unfortunately, the clinical use of TCM metal complexes as anticancer compounds has yielded limited success [41 − 54].

Noteworthily, cryptolepine, the natural product, and its quindoline derivatives have been identified as G-quadruplex ligands and shown significant effects against all kinds of cancer cells [55 − 61]. Only two cryptolepine Zn metal complexes have been reported so far (Figure S1) [61]. We report here, for the first time, Pt(II) complexes with the other quindoline derivatives. In contrast to cryptolepine Zn(II) complexes, two mononuclear Pt(II) compounds, [Pt(BQL1)Cl]Cl (BQL1-Pt) and [Pt(BQL2)Cl]Cl (BQL2-Pt) with [5-(benzo[4, 5]furo[3,2-b]quinolin-11-yloxy)-pentyl]-bis-pyridin-2-ylmethyl-amine (BQL1) and [9-(benzo[4, 5]furo[3,2-b]quinolin-11-yloxy)-nonyl]-bis-pyridin-2-ylmethyl-amine (BQL2), reported in this study, demonstrated in vitro and in vivo antitumor activities against MCF-7, SK-OV-3/DDP, and T-24 cancer cells; these activities were higher than those exhibited by 2,2′-dipicolylamine Pt(II) complex [44] and cisplatin [44]. In addition, we suggested, for the first time, that the cryptolepine Pt(II) complexes induced a high antiproliferative activity via a mitochondrial dysfunction pathway. In reference to dipicolylamine Pt(II) complex and cisplatin, the antiproliferative activity was in the following order: BQL2-Pt > BQL1-Pt > cisplatin > 2,2′-dipicolylamine Pt(II) complex. As expected, compared to 2,2′-dipicolylamine, the neutral BQL1 and BQL2 ligands bearing cryptolepine derivatives increased the planarity and branched chain of the complexes, resulting in the formation of BQL1-Pt and BQL2-Pt with favorable antitumor activities [31 − 54]

Chemistry

[5-(benzo[4, 5]furo[3,2-b]quinolin-11-yloxy)-pentyl]-bis-pyridin-2-ylmethyl-amine (BQ), 2,2′-dipicolylamine Pt(II) complex (Figure S2), and BQL1 ligand were synthesized according to the procedure previously reported by our group [44, 61]. The BQL2 ligand was first synthesized through the synthetic routes shown in Fig. 1, starting from 2-nitrobenzoic acid. Further, BQL1 and BQL2 ligands (1.0 mmol) were refluxed in CH₃OH-DMSO solution (3.5 mL, v:v = 34:1), after which the solid was completely dissolved and treated with 1.0 mmol cis-Pt(DMSO)₂Cl₂ for 48 h to yield the yellow products BQL1-Pt and BQL2-Pt (yield: 82.1% and 88.4%, respectively). BQL1-Pt and BQL2-Pt were fully characterized (Figures S3 − S15).

Next, the solution behavior of BQL1-Pt and BQL2-Pt (2×10^–5 M) in Tris-HCl buffer (containing 1.0% DMSO) was assessed by ESI-MS and UV − vis spectroscopy. As shown in the ESI-MS data in Figures S10-S11, BQL1-Pt and BQL2-Pt had the main peak for [M-Cl]⁺ at m/z = 731.9 and 788.0, respectively, in Tris-HCl solution at 0 h. No change in the m/z values was observed even after 48 h of treatment in Tris-HCl buffer (Figures S8 and S9); thus, concluding that BQL1-Pt and BQL2-Pt were stable in Tris-HCl solution. Their stabilities were further confirmed by UV − vis spectroscopy (Figure S16).

Biology

Cytotoxic activity of complexes

The antiproliferative properties of BQL1, BQL2, BQL1-Pt, and BQL2-Pt were evaluated on several malignant (MCF-7, SK-OV-3/DDP, and T-24) and nonmalignant (HL-7702) cell lines using the colorimetric MTT assay [62 − 73]. Notably, significant differences were observed in the anti-tumor activity of BQL2-Pt with C9 group in the BQL2 ligand and that of BQL1-Pt bearing the C5 group. BQL2-Pt was found to have markedly better antiproliferative activity than BQL1, BQL2, BQL1-Pt, and cis-Pt(DMSO)₂Cl₂ (PtDS) (Table 1). We speculated that the considerable differences in the anti-tumor activities of BQL1-Pt and BQL2-Pt might be a consequence of differences in their hydrocarbon chain length. Further, the IC₅₀ values of BQL1-Pt and BQL2-Pt against T-24 cells were as low as 1.3 ± 0.1 and 0.2 ± 0.2 µM, respectively; these values are approximately 6.5 − 100.7-fold lower than those of cisplatin (13.2 ± 1.3 µM), 2,2′-dipicolylamine Pt(II) complex (20.14 ± 1.09 µM) [44] and cryptolepine Zn metal complexes (5.92 ± 0.35 µM) [61]. More importantly, BQL1-Pt and BQL2-Pt were remarkably toxic to T-24 cells but less toxic to normal HL-7702 cells (> 100 µM).

Table 1

The IC50 (µM) of cryptolepine Pt complexes towards human cells.
	MCF-7	SK-OV-3/DDP	T-24	HL-7702
BQL1	28.1 ± 1.9	62.1 ± 1.1	39.5 ± 0.4	> 100
BQL1-Pt	4.2 ± 0.1	3.3 ± 0.1	1.3 ± 0.1	> 100
BQL2	23.3 ± 0.6	51.1 ± 1.3	34.0 ± 0.9	> 100
BQL2-Pt	1.1 ± 0.1	1.1 ± 0.2	0.2 ± 0.2	> 100
PtDS	> 100	> 100	> 100	> 100
cisplatin (in NaCl)	11.2 ± 0.4	79.5 ± 0.1	13.2 ± 1.3	17.0 ± 0.7
cisplatin(inDMSO)	37.2 ± 0.7	98.7 ± 1.5	38.9 ± 0.2	21.3 ± 0.4

Cellular distribution of the Pt(II) complexes

BQL1-Pt and BQL2-Pt showed excellent cytotoxicity in the anti-proliferative activity studies, which may have been associated with the improved cellular distribution and/or cellular uptake [74 − 79]. Thus, to verify this assumption, we used ICP − MS to study the intracellular Pt(II) content distribution. As shown in Table S1, the accumulation of Pt from BQL2-Pt ((73.69 ± 1.95 ng of Pt)/10⁶ cells) was higher than that from BQL1-Pt ((50.34 ± 2.84 ng of Pt)/10⁶ cells), cisplatin (≤(50.00 ng of Pt)/10⁶ cells) [13], and other TCM metal complexes [31 − 54]. In addition, as shown in Table S1, the concentration of Pt^II inside the mitochondrial fraction released from BQL2-Pt ((45.02 ± 1.45 ng of Pt)/10⁶ cells) at 0.20 µM was higher than that released from BQL1-Pt ((20.92 ± 2.45 ng of Pt)/10⁶ cells) and cisplatin [31 − 54].

Antiproliferative mechanism of Pt(II) complexes

To further understand the antiproliferative mechanism of BQL1-Pt and BQL2-Pt, the expression of five mitochondrial related apoptotic proteins (including caspase-3, Bcl-2, caspase-9, apaf-1, and cytochrome c (cyto c)) was assessed in T-24 cells treated with BQL1-Pt (1.3 µM) and BQL2-Pt (0.2 µM) by using western blotting. As shown in Fig. 2, BQL1-Pt (1.3 µM) and BQL2-Pt (0.2 µM) increased the level of caspase-3, caspase-9, apaf-1, and cytochrome c (cyto c), and decrease the level of Bcl-2. Based on this, we assumed that BQL1-Pt and BQL2-Pt induced apoptosis through the mitochondrial apoptosis pathway, consequently causing DNA damage (Fig. 2 and Table S2), the order of apoptosis induction was as follows: BQL2-Pt > BQL1-Pt > cisplatin [38, 80 − 86].

To further study whether BQL1-Pt and BQL2-Pt induced apoptosis in T-24 cells, flow cytometry analysis was carried out. As shown in Fig. 3A − C, BQL1-Pt and BQL2-Pt efficiently induced apoptosis in T-24 cells, and the apoptotic values were 69.35% and 80.99%, respectively, as compared with that of cisplatin (ca. 13.60%) [80 − 86] and 2,2′-dipicolylamine Pt(II) complex (ca. 15.04%) [44]. Further, BQL2-Pt was selected for an in vivo T-24 xenograft mouse study. When the tumors reached 80 − 190 mm³, the mice were randomly divided into groups and treated with BQL2-Pt (2.0 mg/kg every 2 days) via percutaneous injections. BQL2-Pt inhibited tumor growth in a statistically significant manner with an inhibition ratio (IR) of 55.3% (Table S2 − S4, and Fig. 3D) as compared with untreated mice; this IR was better than that of the cryptolepine Zn metal complexes (IR = 43.0% and 50.7%) [61, 87] and cisplatin (IR = 37.1%) [31 − 54]. Importantly, no evident side effects such as body weight loss (Table S3 − S5) or no animal death were observed in BQL2-Pt-treated groups.

In conclusion, two quindoline Pt^II complexes BQL1-Pt and BQL2-Pt were prepared for the first time in this study. Among them, BQL2-Pt showed the most potent anti-cancer activity, with an IC₅₀ value of 0.2 ± 0.2 µM, and 6.5- and 66.0-fold higher than BQL1-Pt and cisplatin. BQL1-Pt and BQL2-Pt were less toxic against normal HL-7702 cells. Western blotting and cellular uptake studies suggested that BQL1-Pt and BQL2-Pt induced T-24 apoptosis through the mitochondrial apoptosis pathway. Further, BQL2-Pt induced apoptosis by the endogenous pathway and efficiently inhibited T-24 tumor xenograft growth without side effects. In summary, the neutral BQL1 and BQL2 ligands bearing cryptolepine derivatives increased the planarity and branched chain to form BQL1-Pt and BQL2-Pt complexes with favorable antitumor activities.

Synthesis of BQ and BQL1

Synthesis of 11-chlorobenzofuro[3,2-b]quinolone (BQ) and [5-(benzo[4, 5]furo[3,2-b]quinolin-11-yloxy)-pentyl]-bis-pyridin-2-ylmethyl-amine (BQL1) were carried out according to published methods [61].

Synthesis of compound 7

Add compound 5 (3.00 g, 15.1 mmol, 1.00 eq) and compound 6 (3.36 g, 15.1 mmol, 1.00 eq) into MeCN (30.0 mL), and then add KI (2.75 g, 16.6 mmol, 1.10 eq) and K₂CO₃ (3.12 g, 22.6 mmol, 1.50 eq) portionwise into the mixture at 25°C, heat the mixture to 75°C, and stir the mixture at 75°C for 16 hrs. TLC (petroleum ether : ethyl acetate = 0 : 1, product R_f = 0.38) indicated reactant was consumed completely and two new spots formed. The mixture was filtered to get filter liquor, and the reaction mixture was diluted with EtOAc (100 mL) and washed with H₂O (80 mL). The organic layer was washed with H₂O (50 mL) and brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give a brown oil. Finally, ESI-MS and ¹H NMR indicated compound 7 (5.00 g, 11.5 mmol, 76.3% yield) was obtained as a brown oil. ¹H NMR (400 MHz, Chloroform-d): δ 8.55–8.45 (m, 2H), 7.64 (td, J = 7.7, 1.7 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.16–7.09 (m, 2H), 3.79 (s, 4H), 3.62 (t, J = 6.6 Hz, 2H), 2.54–2.49 (m, 2H), 1.56–1.49 (m, 4H), 1.33–1.21 (m, 10H). ESI-MS: m/z = 342.1 for [M + H]⁺. Elemental analysis: calcd (%) for C₂₁H₃₁N₃O: C 73.86, H 9.15, N 12.30; found: C 73.85, H 9.17, N 12.29.

Synthesis of [9-(benzo[4, 5]furo[3,2-b]quinolin-11-yloxy)-nonyl]-bis-pyridin-2-ylmethyl-amine (BQL2)

Add compound 7 (1.00 g, 2.93 mmol, 1.20 eq) into DMA (10.0 mL), add NaH (195 mg, 4.88 mmol, 60% purity, 2.00 eq) portionwise into the mixture at 25°C, stir the mixture at 25°C for 0.2 h, and then add BQ (619 mg, 2.44 mmol, 1.00 eq) into the mixture at 25°C, heated the mixture to 70°C, and stir the mixture at 70°C for 1.5 h. LC-MS showed compound BQ was consumed completely and one main peak with desired m/z. In addition, TLC (petroleum ether : ethyl acetate = 1 : 1, product R_f = 0.43) indicated reactant was consumed completely and two new spots formed. The mixture was quenched with saturated NH₄Cl (100 mL) and extracted with EtOAc (150 mL × 2). The organic phases were washed with water (80 mL × 3), dried over Na₂SO₄, and filtered and concentrated in vacuum. Purify the residue by column chromatography (SiO₂, petroleum ether : ethyl acetate = 50 : 1 to 1 : 1) and evaporate to obtain desired product. Finally, ESI-MS, ¹H NMR and ¹³C NMR indicated BQL2 (2.60 g, 4.46 mmol, 61.0% yield, 95.9% purity) was obtained as a brown oil. ¹H NMR: (400MHz, CDCl3-d) δ 8.48 (br d, J = 4.4 Hz, 2H), 8.35 (t, J = 9.2 Hz, 2H), 8.18 (d, J = 8.6 Hz, 1H), 7.68 (dt, J = 1.3, 7.7 Hz, 1H), 7.64–7.57 (m, 3H), 7.55–7.46 (m, 3H), 7.46–7.38 (m, 1H), 7.10 (dd, J = 5.5, 6.6 Hz, 2H), 4.94 (t, J = 6.5 Hz, 2H), 3.78 (s, 4H), 3.47 (s, 1H), 2.57–2.44 (m, 2H), 2.02–1.87 (m, 2H), 1.65–1.44 (m, 4H), 1.42–1.32 (m, 2H), 1.32–1.19 (m, 6H). ¹³C NMR: (101MHz, CDCl3-d) δ 160.12, 158.63, 149.15–148.75 (m, 1C), 147.29, 144.22, 136.37, 134.48, 130.59, 128.48 (d, J = 5.9 Hz, 1C), 124.75, 123.48, 123.11, 122.84, 122.37 (d, J = 18.3 Hz, 1C), 121.85, 121.38, 111.97, 72.95, 60.48, 54.53, 50.57, 30.09, 29.63–29.17 (m, 1C), 27.19 (d, J = 24.9 Hz, 1C), 25.91. ESI-MS: m/z = 559.3 for [M + H]⁺. Elemental analysis: calcd (%) for C₃₆H₃₈N₄O₂: C 77.39, H 6.86, N 10.03; found: C 77.38, H 6.88, N 10.02.

Synthesis of BQL1-Pt and BQL2-Pt

The BQL1 and BQL2 ligands (1.0 mmol) was refluxed in CH₃OH-DMSO solution (3.5 mL, v:v = 34:1), which after the solid was completely dissolved, was treated with 1.0 mmol cis-Pt(DMSO)₂Cl₂ for 48 h forming yellow product BQL1-Pt and BQL2-Pt (yield: 82.1% and 88.4%), respectively.

Data for BQL1-Pt: Yield: 82.1%. ESI-MS: m/z = 731.9 for [M-Cl]⁺ ([Pt(BQL1)Cl]⁺, 10 mM pH 7.35 Tris-HCl buffer solution, 5% DMSO). Elemental analysis: calcd (%) for C₃₂H₃₀Cl₂N₄O₂Pt: C 50.01, H 3.93, N 7.29; found: C 50.00, H 3.95, N 7.28. ¹H NMR (500 MHz, DMSO-d6) δ 8.76 (dd, J = 5.8, 1.6 Hz, 2H), 8.29–8.22 (m, 3H), 8.20 (dd, J = 8.9, 1.2 Hz, 1H), 8.14–8.10 (m, 1H), 7.79 (d, J = 7.9 Hz, 2H), 7.78–7.72 (m, 3H), 7.65–7.60 (m, 2H), 7.57 (ddd, J = 8.2, 6.7, 1.2 Hz, 1H), 7.53 (ddd, J = 7.9, 6.5, 1.5 Hz, 1H), 5.41 (d, J = 15.9 Hz, 2H), 4.89 (d, J = 15.8 Hz, 2H), 4.79 (t, J = 6.1 Hz, 2H), 3.15–3.07 (m, 2H), 1.77 (dq, J = 12.2, 6.3 Hz, 2H), 1.65 (dq, J = 13.8, 7.1 Hz, 2H), 1.51 (q, J = 7.8 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d6) δ 166.34, 158.54, 149.44, 148.79, 147.20, 143.63, 141.73, 134.33, 131.75, 129.11, 128.93, 125.76, 125.61, 124.41, 123.91, 122.87, 122.51, 122.30, 121.12, 112.87, 72.78, 68.29, 64.57, 40.92, 40.51, 40.34, 40.18, 40.01, 39.84, 39.68, 39.51, 29.47, 27.13, 22.94.

Data for BQL2-Pt: Yield: 88.4%. ESI-MS: m/z = 788.0 for [M-Cl]⁺ ([Pt(BQL2)Cl]⁺, 10 mM pH 7.35 Tris-HCl buffer solution, 5% DMSO). Elemental analysis: calcd (%) for C₃₆H₃₈Cl₂N₄O₂Pt: C 52.43, H 4.64, N 6.79; found: C 52.42, H 4.67, N 6.78. ¹H NMR (500 MHz, DMSO-d6) δ 8.79 (dt, J = 6.0, 1.8 Hz, 2H), 8.32–8.24 (m, 4H), 8.17–8.11 (m, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.80–7.72 (m, 3H), 7.68–7.65 (m, 2H), 7.55 (dddd, J = 30.5, 8.0, 6.9, 1.2 Hz, 2H), 5.39 (d, J = 15.7 Hz, 2H), 4.95–4.81 (m, 4H), 3.03–2.98 (m, 2H), 1.84 (dq, J = 13.6, 6.7 Hz, 2H), 1.46 (q, J = 10.9, 7.2 Hz, 4H), 1.25 (t, J = 7.2 Hz, 2H), 1.16–1.07 (m, 6H). ¹³C NMR (126 MHz, DMSO-d6) δ 166.36, 158.56, 149.47, 148.80, 147.24, 143.78, 141.78, 134.38, 131.72, 129.10, 128.95, 125.81, 125.57, 124.39, 123.93, 122.90, 122.49, 122.28, 121.20, 112.86, 73.06, 68.33, 64.68, 40.94, 40.53, 40.36, 40.20, 40.03, 39.86, 39.69, 39.53, 29.81, 29.09, 29.06, 28.90, 27.44, 26.24, 25.69.

Methods

A total of 1.0 mM cisplatin was prepared in 0.154 M NaCl and DMSO solution [25]. For materials and the detailed methods of BQL1-Pt (1.3 µM) and BQL2-Pt (0.2 µM) were carried out according to Qin, Liang, Lim and Gou published methods [1, 61, 74].

Acknowledgements

We thank the National Natural Science Foundation of China (21867017) and the Natural Science Foundation of Guangxi (2020GXNSFAA297077).

Compliance with ethical standards

Conflict of interest The authors declare that they have no conflict of interest.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Editorial decision: Major Revision
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Strong In Vitro And Vivo Cytotoxicity Of Two Platinum(II) Complexes With Cryptolepine Derivatives

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Abstract

Figures

Introduction

Results And Discussion

Chemistry

Biology

Cytotoxic activity of complexes

Cellular distribution of the Pt(II) complexes

Antiproliferative mechanism of Pt(II) complexes

Conclusion

Material And Methods

Synthesis of BQ and BQL1

Synthesis of compound 7

Synthesis of [9-(benzo[4, 5]furo[3,2-b]quinolin-11-yloxy)-nonyl]-bis-pyridin-2-ylmethyl-amine (BQL2)

Synthesis of BQL1-Pt and BQL2-Pt

Methods

Declarations

References

Supplementary Files

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Version 1