The primary motivation behind the focus on DPs in pharmaceuticals is ‘safety’ through ‘quality’. A fraction of DPs may even be genotoxic, which raises further safety concerns. DPs may result in genetic mutations that increase the likelihood of causing cancer or other toxic effects. LFT is known to form impurities under stressed conditions during stability testing (Kumar and Chalannavar 2022). The developed RP-HPLC-DAD method was successfully employed in the stressed study. LFT showed significant degradation under acidic stress conditions at 80 ºC (Figure S2). Upon acidic exposure with 0.1N, 1N, 3N, and 5N HCl, the percent degradation was significantly increased with the collective strength of hydrochloric acid. Significant degradation peak was observed with an oxidative agent called hydrogen peroxide (5%) at the same retention time of one of the acidic degradation products (Figure S3). No significant degradation of LFT was expressed in neutral hydrolysis at both room and higher temperatures. LFT shows a degradation peak in the alkaline degradation sample initially with the retention times as matched with the acidic degradation sample. To check whether the degradants are formed in acidic or alkaline conditions, the individual degradation samples were injected into the LC without neutralization. No degradation peak was observed in the alkaline sample, whereas in the acidic degradation sample, two degradation peaks were observed. This confirms that degradation products are formed because of exposure to acidic pH conditions. Two degradants were eluted before the LFT peak (Figure S2), suggesting the LFT is degrading into polar moieties. No degradation was observed in UV and photo degradation studies, which confirm that LFT is UV and photo-stable drug (Figure S3).
To resolve the LFT DPs, we have considered to standardize a novel, MS-compatible, simple approach in the reverse phase chromatography. Preliminary trials were carried out using various mobile phase compositions, such as 100% water, methanol, acetonitrile, and formic acid in water and acetonitrile (0.1% v/v). Various chromatographic method settings, such as mobile phase gradient composition, loading volume, dimensions of the stationary phase, detection wavelength, flow rate, and analysis duration were tried. The RP-HPLC-DAD approach was standardised as discussed in the section 2.2, to resolve LFT and the main degradation products found in acidic hydrolytic conditions.
As a part of the stability indicating assay method validation, the linearity of the developed method was established by regression analysis. The slope (m), intercept (C), and correlation coefficient (R2) of LFT were determined (Table 1). The calibration curve for LFT under the optimized method was plotted and represented in Figure S4. LOD and LOQ of the optimised method were determined from the calibration curve using the standard error of intercept and slope (Table 1). System suitability testing was performed to check whether the instrument output is precise or not. The % RSD of retention duration, peak area, resolution between the peaks, theoretical plates, and tailing factor were taken as part of the study (Table 1). The accuracy (% recovery) of LFT was found between the ranges of 85 and 115% (Table 2). The control chart representation of the % recovery results of the LFT is portrayed in Figure S4. As a precision test, % RSD was obtained from the six replicates as 0.95%. The precision results (% RSD) of LFT within a day and between the days are given in Table 2. Robustness was established by setting involuntary changes in chromatographic conditions such as flow rate, column oven temperature, and buffer composition. The effect of such alterations on retention duration, peak response, asymmetry, and theoretical plates was determined to confirm the robustness of the method. The result (Table S1) signifies that the developed method is reliable and can be used for the analysis of LFT and its degradation products. Analytical solutions (LFT in acetonitrile: water 1:1 (v/v)) were stable, and their stability was verified on comparison of the analytical solution to the standard at moderate temperatures 25 ºC (± 2 ºC), 4 ºC (± 2 ºC), -20 ºC (± 2 ºC), and − 80 ºC (± 2 ºC) for 48 h and the results were tabulated in Table S2. From the stability of the analytical solution, it may be inferred that the solutions will be steady for two days.
Table 1
Assay parameters for the determination of LFT under the optimized RP-HPLC method
Parameter
|
Result
|
Range
|
30–500 µg/mL
|
Slope
|
45.45
|
Coefficient of intercept
|
650.01
|
Correlation coefficient (R2)
|
0.999
|
Standard error of intercept
|
137.50
|
Limit of detection (LOD)
|
10.43 µg/mL
|
Limit of quantification (LOQ)
|
31.62 µg/mL
|
System suitability testing
|
RSD% a (mean ± SD)
|
0.04 (5.53 ± 0.002) min
|
RSD% b (mean ± SD)
|
0.23 (5169.25 ± 12.14)
|
RSD% c (mean ± SD)
|
1.46 (0.97 ± 0.01)
|
RSD% d (mean ± SD)
|
1.82 (17315 ± 316.54)
|
Note: RSD% a: Retention time, RSD% b: peak area, RSD% c: tailing factor, RSD% d: theoretical plates, SD: standard deviation, RSD: relative standard deviation
|
Table 2
Accuracy and precision results of the optimized method for the determination of LFT
Accuracy level
|
% Recovery
(mean ± SD)
|
Intraday precision
% RSD (mean ± SD)
|
Inter-day precision
% RSD (mean ± SD)
|
80%
|
91.97 ± 1.33
|
0.99 (4705.28 ± 26.92)
|
1.17 (4707.59 ± 31.80)
|
100%
|
100.76 ± 0.23
|
0.14 (5197.66 ± 7.59)
|
0.42 (5210.71 ± 22.08)
|
120%
|
103.67 ± 1.41
|
1.138 (6703.32 ± 87.66)
|
1.08 (6712.17 ± 83.89)
|
Subsequent to the HPLC analysis, the degraded sample fractions were collected individually based on the retention times of the main degradation products and the LFT by bypassing from the waste for replicated injections. LC-ESI-MS analysis of the collected fractions was performed using Thermo Scientific’s, Hypersil GOLD™ C18 column (15 × 4.6 mm, 3 µ) as a stationary phase with a flow rate of 0.6 mL/min. The employed ionisation source is ESI in positive mode. The molecular masses of the LFT and its two degradation products were found to be m/z 615.0745, m/z 471.0539, and m/z 161.0243, respectively, and those were matched with the reported literature.(Kumar and Chalannavar 2022) The positive mode ESI-MS/MS spectrum of LFT showed the daughter ions at m/z 372.0187 (deduction of C10H13NO4S from m/z 615.0745), m/z 227.9988 (deduction of C9H4O2 from m/z 372.0189), and m/z 145.0289 (deduction of C9H7Cl2NO from m/z 372.0187). LFT has been degraded into two degradation products, DP1 and DP2, in acidic conditions. DP1 is the Lifitegrast amine, whereas DP2 is the acid. The mass accuracy data was shown in Table S3. As reported in the literature(Kumar and Chalannavar 2022) regarding potential fragmentation pathways for Lifitegrast degradants, this research does not go to great lengths into mass fragmentation.
Gaussian 16 was used to perform DFT calculations at the B3LYP/6–31 + G(d) level of theory (Foresman et al. 1996). The enthalpy of the two competing hydrolysis pathways (Fig. 1) was calculated both in the gaseous state and water medium (using the CPCM model) (Tomasi et al. 2005). An amide hydrolysis reaction enthalpy in gas-phase and water medium at B3LYP/6–31 + G(d) level was performed on the Lifitegrast.
The analysis reveals two distinct pathways, labelled as A and B, each characterized by their respective thermodynamic properties in both gas phase and a water medium. For pathway A, in the gas phase, the enthalpy change (ΔH) is calculated to be 0.07 kcal/mol, while the standard Gibbs free energy change (ΔG°) is 1.21 kcal/mol. When transitioning to a water medium, the enthalpy change (ΔHw) increased to 1.61 kcal/mol, and the standard Gibbs free energy change (ΔG°w) becomes 2.76 kcal/mol. In contrast, pathway B exhibits significantly different thermodynamic values. In the gas phase, pathway B has a ΔH 9.45 kcal/mol and a ΔG° of 8.91 kcal/mol. When considered in a water medium, ΔHw decreases slightly to 8.73 kcal/mol, while ΔG°w is reduced to 8.11 kcal/mol. These results have shown that the amide hydrolysis pathway ‘A’ leading to the formation of the Lifitegrast-amine 1 impurity is only marginally endothermic. Whereas, pathway B, leading to the formation of alternative impurities (Lifitegrast acid and corresponding amino acid, Fig. 1), is considerably more endothermic than pathway A. Thus, these reaction enthalpy calculations correctly explain the experimental observation of the preferential formation of Lifitegrast-amine 1 and benzofuran-6-carboxylic acid (DP1, and DP2 respectively).
Synthesis and characterization of DP1
(S)-2-((tert-butoxycarbonyl)amino)-3-(3-(methylsulfonyl)phenyl)propanoic acid
(S)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (2.0 g, 5.83 mmol) was dissolved in DMSO (8 mL, 4 vol) and reacted with sodium methane sulfonate (1.96 g, 19.24 mmol), CuI (1.1 g, 5.83 mmol), and L-Proline (1.07 g, 9.32 mmol). Potassium carbonate (800 mg, 5.83 mmol) was also added to this at a moderate temperature under a nitrogen atmosphere. The resulting reactant was kept for stirring at 110°C for 16 h. TLC has shown the formation of polar spots along with minor unreacted starting material. The reaction mixture was gradually cooled to room temperature following the completion of the reaction. The 10% citric acid solution was added and allowed to stir for 10 min, followed by filtration through a celite pad and washing with dichloromethane (DCM). The filtered solution was extracted with DCM (3 x 100 mL). Pooled all organic layers and washed with ammonium chloride solution (50 mL) followed by sodium bisulfite solution (50 mL). The organic layer was separated, concentrated, and dried to obtain a residue. The obtained residue was triturated with diethyl ether to acquire a (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(methylsulfonyl)phenyl)propanoic acid (Compound-1) (2.0 g), as a pale-yellow solid.
Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(methylsulfonyl)phenyl)propanoate
The (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1.0g, 2.91 mmol) (Compound-1) was dissolved in DCM (5 mL, 5vol), EDC. HCl (CAS # 25952-53-8 ) (550 mg, 2.91 mmol), and DMAP (35 mg, 0.29 mmol) were also added to it, followed by the addition of benzyl alcohol (346 mg, 3.20 mmol) at 0°C with continuous agitation. The resultant reaction mixture was kept for stirring at 5–10°C for 3 h. Subsequent to the completion of the reaction, it was allowed to gradually warm to a moderate temperature. The reaction mixture was quenched with water and extracted with DCM (3 x 30 mL). Pooled all organic layers and washed with brine solution (1 x 50 mL), and the organic layer was separated, concentrated, and dried to acquire residue. The crude compound was purified by silica gel column chromatography in DCM and methanol. Required fractions were gathered and concentrated under lower pressure to obtain benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(methylsulfonyl)phenyl)propanoate (Compound-2) (800 mg) as an off-white solid.
Benzyl (S)-2-amino-3-(3-(methylsulfonyl)phenyl)propanoate hydrochloride
The benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(methylsulfonyl)phenyl)propanoate (Compound-2) (500 mg, 1.15 mmol) was solubilized in DCM (5 mL), and 1,4-Dioxane.HCl (4 mL) was spiked dropwise with continuous stirring at 0–5°C. The resulting mixture was kept at a moderate temperature for 2 h under continuous stirring. TLC visualised a non-polar spot, which indicated the consumption of starting material. Subsequent to the completion of the reaction, the excess solvent was vaporised to obtain a residue, and it was triturated using diethyl ether to get benzyl (S)-2-amino-3-(3-(methylsulfonyl)phenyl)propanoate hydrochloride (Compound-3) (350 mg) as a light brown solid.
Tert-butyl(S)-6-((1-(benzyloxy)-3-(3-(methylsulfonyl)phenyl)-1-oxopropan-2 yl)carbamoyl)-5-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate
The benzyl (S)-2-amino-3-(3-(methylsulfonyl)phenyl)propanoate hydrochloride (Compound-3) (500 mg, 1.35 mmol) was solubilized in DMF (5 mL, 10 vol), followed by adding DIPEA (611 mg, 4.72 mmol), and HATU (566 mg, 1.48 mmol) under stirring, followed by 2-(tert-butoxycarbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (Intermediate-1) (514 mg, 1.48 mmol) at 0°C. The resultant mixture was kept at a moderate temperature for 16 h under constant stirring. TLC visualised a non-polar spot, which indicated the consumption of starting material. Subsequent to the completion of the reaction, the reactant mixture was quenched with water and extracted with ethyl acetate (2 x 50 mL). Pooled all organics and washed with brine solution (1 x 50 mL). The organic phase was separated, concentrated, and dried to obtain residue. The crude residue was purified using silica gel column chromatography and eluted in DCM and methanol. Fractions were gathered and concentrated under lower pressure to achieve tert-butyl (S)-6-((1-(benzyloxy)-3-(3-(methyl sulfonyl) phenyl)-1-oxopropan-2-yl)carbamoyl)-5,7-dichloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (Compound-4) (400 mg) as an off-white semi-solid.
( S )-2-(2-(tert-butoxycarbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid: The tert-butyl (S)-6-((1-(benzyloxy)-3-(3-(methylsulfonyl)phenyl)-1-oxopropan-2-yl)carbamoyl)-5,7-dichloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (Compound-4) (2.6 g, 3.93 mmol) was dissolved in methanol: THF (1:1; 40 mL), followed by the addition of 10% Pd-C (520 mg, 20% w/w). The resulting reaction mixture was kept at room temperature under an H2 gas atmosphere (balloon pressure) for 16 h. TLC visualised a non-polar spot, which indicated the consumption of starting material. Subsequent to the completion of the reaction, the resultant was filtered through a celite pad, followed by washing with methanol (20 mL). The filtrate was concentrated under lower pressure to obtain a residue. The crude compound was made pure by reverse-phase column chromatography using a C18 column with acetonitrile/water as the mobile phase. Required fractions were gathered and concentrated under lower pressure to obtain (S)-2-(2-(tert-butoxycarbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (Compound-5) (1.5 g) as an off-white solid.
(S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (LFT DP1)
The (S)-2-(2-(tert-butoxycarbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (Compound-5) (1.5 g, 2.63 mmol) was dissolved in dioxane (15 mL), followed by adding 4N 1,4-Dioxane.HCl (10.0 mL) dropwise at 0–5°C. The resultant reaction mixture was kept at a moderate temperature for 2 h under continuous stirring. TLC has shown the completion of the reaction of compound-5 and the formation of the polar spots. The excess solvent has been vaporised to obtain a residue, and it was triturated with diethyl ether to obtain crude (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (Compound-6) (1.0 g) as a light brown semi-solid. The crude compound was purified by reverse-phase column chromatography using the C18 column as the stationary phase and acetonitrile/water as the mobile phase. Desired fractions were collected and lyophilized to obtain (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (LFT DP1) (180 mg) as an off-white solid. The compound was confirmed by mass spectrometry, 1HNMR, IR, and HPLC techniques.
LC-ESI-MS full-scan mass spectra of the LFT and the synthesised DP1 have observed molecular ion peaks at [M + H] 615.0748 and 471.0536, respectively (Figure S5). The positive mode LC-ESI-MS scan of the LFT DP1 revealed the daughter ions at m/z 227.9975, m/z 200.0026, and m/z 165.0342. The ESI-MS fragments were found in accordance with the reported article.(Kumar and Chalannavar 2022) It confirms, the synthesised compound is DP1. In the NMR spectra, the peaks at 2.50 ppm and 39.50 ppm corresponded to DMSO-d6 for 1H and 13C, respectively. The chemical shifts of lifitegrast and DP1 are shown in Table 3. The lack of many signals of lifitegrast in the degradation products observed in the spectrum confirms this purpose. The NMR studies of DP1 have revealed that it has 20 hydrogens and 20 carbons (Figures S6, S7, S8, and S9). The chemical shifts are in good agreement with the proposed structures. FT-IR (KBr pellet) has shown the N-H stretching 3340.04cm-1, the C-H stretching 3022.49cm-1, and the C = O stretching 1648.83cm-1 (Figure S14). The absence of certain functional groups of lifitegrast supports the confirmation of the formation of DP1. The HPLC confirmation of DP1 was conducted using the validated RP-HPLC-DAD method by matching to the retention times. The resultant chromatogram of the DP1 is portrayed in Figure S15.
Characterization of DP2
The current research is not focused on the synthesis of DP2. However, since DP2 has been used as a starting material in the production of lifitegrast (Yerrabelly JR, Kommera R, Reddy KV, Reddy GV 2020), the commercial sample has been procured and confirmed as DP2 using various analytical advancements namely, mass spectrometry, NMR studies, HPLC analysis, and IR spectroscopy. LC-ESI-MS full-scan mass spectrum of the DP2 has found a precursor ion peak at [M-H] at 161.0242. The negative mode LC-ESI-MS spectrum of the LFT DP2 showed the daughter ion at m/z 117.0346. In NMR spectra, the peaks at 2.50 ppm and 39.50 ppm corresponded to DMSO-d6 for 1H and 13C, respectively. The chemical shifts of lifitegrast and DP2 are shown in Table 3. The NMR studies of DP2 have revealed that it has 6 hydrogens and 9 carbons (Figures S10, S11, S12, and S13). The chemical shifts are in agreement with the proposed structures. The DP2 is benzofuran 6-carboxylic acid, and it exhibits characteristics of both alcohols and ketones due to the presence of O-H bond and the C = O bond. FT-IR (KBr pellet) spectrum of the DP2 has shown the O-H stretching of 3435.45 cm− 1, the C-H stretching of 2925.75 cm− 1, and the C = O stretching of 1680.10 cm− 1 (Figure S14). The HPLC confirmation of DP2 was conducted using the standardised RP-HPLC-DAD method. The resultant chromatogram of the DP2 is portrayed in Figure S15.
Table 3
Carbon and proton chemical shift values and their splitting pattern of the lifitegrast and its two acidic hydrolytic degradation products (DP1 and DP2)
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)
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)
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![](data:image/png;base64,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)
|
A*
|
13Cδ
|
A#
|
1Hδ
|
A*
|
13Cδ
|
A#
|
1Hδ
|
A*
|
13Cδ
|
A#
|
1Hδ
|
13
|
172.07
|
15
|
12.88 (brs)
|
13
|
172.77
|
16
|
8.57–8.59 (d)
|
10
|
167.40
|
11
|
12.98 (s)
|
30
|
169.50
|
16
|
9.01–9.03 (d)
|
17
|
163.23
|
10
|
7.83 (s)
|
2
|
153.82
|
3
|
8.20 (d)
|
17
|
163.56
|
39
|
8.12–8.13 (d)
|
5
|
140.38
|
6
|
7.73–7.75 (d)
|
8
|
149.05
|
8
|
8.13 (s)
|
34
|
153.64
|
33
|
7.86 (s)
|
9
|
139.87
|
8
|
7.63–7.65 (d)
|
1
|
131.43
|
5
|
7.86–7.88 (dd)
|
39
|
147.76
|
36,37, 21,10
|
7.66–7.78 (m)
|
22
|
137.04
|
7
|
7.51–7.55 (t)
|
4
|
126.99
|
6
|
7.75–7.77 (d)
|
5
|
140.63
|
7
|
7.54–7.58 (t)
|
19
|
134.77
|
21
|
7.20 (s)
|
5
|
123.99
|
7
|
7.07–7.08 (m)
|
9
|
139.10
|
6, 8
|
7.31–7.33 (m)
|
8
|
134.68
|
12
|
4.59–4.64 (m)
|
6
|
121.17
|
|
|
22
|
137.05
|
38
|
7.04–7.05 (d)
|
23,24
|
131.17
|
29
|
3.90 (s)
|
3
|
112.39
|
|
|
35
|
134.53
|
12, 23
|
4.74–4.80 (m)
|
20
|
129.04
|
11,27
|
(3.02–3.08) (3.25–3.30) (m)
|
7
|
107.03
|
|
|
19
|
134.47
|
25
|
3.64 (brs)
|
7
|
128.00
|
1
|
3.14 (s)
|
|
|
|
|
8
|
131.66
|
11
|
(2.99–3.05) (m) (3.27–3.28) (m)
|
10
|
127.86
|
26
|
2.60 (t)
|
|
|
|
|
27
|
131.60
|
1
|
3.15 (s)
|
21
|
125.59
|
|
|
|
|
|
|
28
|
131.13
|
26
|
2.77 (t)
|
6
|
124.78
|
|
|
|
|
|
|
20
|
129.26
|
|
|
12
|
54.41
|
|
|
|
|
|
|
32
|
128.67
|
|
|
1
|
45.31
|
|
|
|
|
|
|
7
|
128.38
|
|
|
29
|
43.65
|
|
|
|
|
|
|
10
|
127.73
|
|
|
27
|
41.31
|
|
|
|
|
|
|
21
|
~ 125.80
|
|
|
11
|
37.07
|
|
|
|
|
|
|
6
|
125.06
|
|
|
16
|
25.10
|
|
|
|
|
|
|
36
|
122.02
|
|
|
|
|
|
|
|
|
|
|
37
|
121.44
|
|
|
|
|
|
|
|
|
|
|
33
|
110.34
|
|
|
|
|
|
|
|
|
|
|
38
|
106.85
|
|
|
|
|
|
|
|
|
|
|
12
|
54.92
|
|
|
|
|
|
|
|
|
|
|
23
|
53.06
|
|
|
|
|
|
|
|
|
|
|
1
|
43.62
|
|
|
|
|
|
|
|
|
|
|
25
|
~ 39.50
|
|
|
|
|
|
|
|
|
|
|
11
|
36.35
|
|
|
|
|
|
|
|
|
|
|
26
|
~ 23.50
|
|
|
|
|
|
|
|
|
|
|
A*: Carbon assignments; A#: Proton assignments; δ: Chemical shift (ppm); brs: broad singlet, s: singlet, d: doublet, t: triplet, m: multiplet
|
Employing the Swiss ADME prediction tool, both LFT degradation products were found to comply with Lipinski's rule of five (Susanna et al. 2022), (molecular weight < 500, log Po/w ≤ 5, donor hydrogen bonds ≤ 5, accept hydrogen bonds ≤ 10) and to have the appropriate ADME properties (Table 4). As the log S and log Po/w of DP1 and DP2 did not surpass 0.5 and 6, respectively, they were expected to have good aqueous solubility (log S) as well as an octanol/water partition coefficient (log Po/w). Furthermore, both DPs were expected to have high gastrointestinal (GI) absorption. They were also found not to possess any pan-assay interference structures (PAINS).
Table 4
In silico toxicity predictions of Lifitegrast DP1 & DP2 using SWISS ADME and DEREK predictions
SWISS ADME Predictions
|
|
Description
|
DP1
|
DP2
|
Physico-chemical Descriptors
|
Molecular formula
|
C20H20Cl2N2O5S
|
C9H6O3
|
Molecular weight
|
471.35
|
162.14
|
No. of Heavy atoms
|
30
|
12
|
No. of aromatic Heavy atoms
|
12
|
9
|
Rotatable bonds
|
7
|
1
|
Acceptor HB
|
6
|
3
|
Donor HB
|
3
|
1
|
Molar refractivity
|
117.77
|
43.17
|
TPSA (A2)
|
120.95
|
50.44
|
Lipophilicity
|
Log Po/w
|
2.24
|
1.65
|
Solubility
|
Log S
|
-2.85
|
-2.50
|
Pharmacokinetics
|
GI Absorption
|
High
|
High
|
|
BBB
|
No
|
Yes
|
|
P-gp substrate
|
Yes
|
No
|
|
CYP-1A2 inhibitor
|
No
|
Yes
|
|
Log Kp (Skin permeation)
|
-8.89 cm/s
|
-5.98 cm/s
|
Medicinal Chemistry
|
PAINS
|
0
|
0
|
DEREK- Predictions
|
Description
|
DP1 alert
|
DP2 alert
|
Glucocorticoid receptor agonism in mammal
|
Plausible
|
-
|
Mutagenicity in vitro in bacterium
|
Inactive
|
Inactive
|
Skin sensitization in mammals
|
Non-sensitizer
|
Non-sensitizer
|
Teratogenicity in mammals
|
Equivocal
|
-
|
Carcinogenicity in mammals
|
-
|
Equivocal
|
Hepatotoxicity in mammals
|
-
|
Plausible
|
Employing the DEREK software, various toxicities like skin sensitization, mutagenicity, carcinogenicity, and hepatotoxicity potential of the LFT degradants were predicted (Table 4). DP1 is shown to have glucocorticoid receptor agonism in mammals due to the alert of N-Phenethylbenzamide or a derivative (Figure S16). If a chemical contains this alert, then it is considered plausible that the chemical will cause glucocorticoid receptor agonism in mammals and impossible in bacteria. If a chemical contains a glucocorticoid receptor agonism alert, then it is considered equivocal that the chemical will cause teratogenicity (irreversible deleterious structural malformation in fetuses) in mammals and impossible in bacteria (Betageri R, Zhang Y, Zindell RM, Kuzmich D, Kirrane TM, Bentzien, J.; Cardozo, M.; Capolino AJ, Fadra TN, Nelson RM 2005). DEREK also predicted that there would be no alert for skin sensitization, mutagenicity, carcinogenicity, or hepatotoxicity in the case of DP1.
Regarding DP2, it is inactive to the mutagenicity in vitro in the bacterium and a non-sensitizer in cases of skin sensitization in mammals. However, it was showing adverse toxicity including carcinogenicity and hepatotoxicity potential, in mammal species. DP2 is predicted to produce alert 542, which describes the hepatotoxicity of furan derivatives (Fig. 16) (McMurtry RJ 1997). The furan's oxidative ring opening is thought to be the cause of toxicity because it creates reactive intermediates that can alkylate proteins or bind to DNA.(Dalvie et al. 2002) DP2 is also predicted to produce alert 560, and it describes the carcinogenicity of furans according to the furan (toxicophore I) and furyl methanol (toxicophore II) (National Toxicology Program 1993). The term 'carcinogen' refers to a substance that is cytotoxic and is capable of causing DNA damage, eventually leading to cancer. The liver is the primary target organ for furan carcinogenicity. The mode of action is not clearly understood but is thought to involve metabolic activation to generate reactive metabolites, which subsequently may induce tumors by either genotoxic or epigenetic mechanisms, and various hypotheses have been postulated. For the furans (toxicophore I), the metabolic activation is generally considered to proceed via cytochrome P450 (CYP450) oxidation (Kedderis LS 1999). In vitro studies with rat liver microsomes trapped and identified the ring opened metabolite of furan, cis-2-butene-1,4-dial as the bis-semicarbazone adduct (Chen et al. 1995). This reactive metabolite is thought to be formed from furan via an epoxide intermediate, highlighting the likely involvement of CYP450 (Kedderis LS 1999). Cis-2-butene-1,4-dial has been found to bind to proteins and nucleosides (Burka et al. 1991; Byrns et al. 2002) leading to cytotoxicity followed by compensatory cell proliferation, increasing the likelihood of tumour induction (Chen et al. 1995). Furthermore, it was observed that cis-2-butene-1,4-dial detaches mitochondrial oxidative phosphorylation, reducing the supply of ATP, which leading to the activation of double-stranded DNA endonucleases and subsequent double-stranded DNA breaks (Kedderis LS 1999). Additionally a partial genotoxic mechanism cannot be ruled out. Cis-2-butene-1,4-dial has been demonstrated to exert mutagenic activity in the Ames test (Peterson LA, Naruko KC 2000) as well as in the mouse lymphoma assay (Kellert M, Brink A, Richter I, Schlatter J 2008). Moreover, furan-induced rodent tumours showed an increased frequency of Ha-ras-1 gene mutations, which are thought to induce cell proliferation (Johansson E, Reynolds S, Anderson M 1997). For furyl methanol derivatives (toxicophore II), the metabolic activation is thought to involve sulphotransferase conjugation (Monien BH, Frank H, Seidel A 2009). Recent in vivo studies in mice with HMF indicated that it is transformed to 5-sulphooxymethylfurfural (SMF) by hepatic sulphotransferases (Monien BH, Frank H, Seidel A 2009). This allylic sulphate ester can go on to form highly reactive intermediates such as the carbenium ion, which may bind directly to DNA. In support of the latter assertion, SMF has been shown to bind to DNA in cell-free systems and to exert mutagenic activity in bacterial TA100 revertant assay (Surh YJ, Liem A, Miller JA 1994). Considering this hypothetical knowledge on the cell related toxicity (teratogenicity of DP1, and carcinogenicity & hepatotoxicity of DP2) of the degradation products, in vitro toxicity studies were considered for both DPs to uncover the cytotoxicity potential of DPs. Testing for cytotoxicity is essential part to keep people safe. Additionally, it assists companies in ensuring that their products are safe. If something is labelled cytotoxic, a person will know that they need to take precautions when they are exposing to it. Consequently, the in vitro cytotoxicity study of synthesized DP1 and procured DP2 was carried on the HCE cell line using MTT assay.
Cell development and proliferation are significantly influenced by growth factors, which are distinct cell signaling molecules. The utilization of pure, premium proteins has been shown to have significant advantages for cell cultures. Prior to the experiment, the HCE cells were cultured in DMEM medium. FBS served as a supplement, in providing the nutrients, trace elements and hormone factors for proliferation and growth of the cell. Insulin served as a growth factor with mitogenic and anti-apoptotic properties. Strong mitogenic activity of EGF is involved in the development, proliferation, and maturation of different types of epidermal and epithelial tissues both in vivo and in vitro, as well as in the proliferation of certain fibroblasts in cell culture. Bacterial contamination in cell culture media is prohibited with the use of Penicillin-Streptomycin solution (Gospodarowicz and Moran 1976; Hyun SW, Kim BR, Lin D, Hyun SA, Yoon SS, Seo JW 2018). The cytotoxicity result upon the treatment of DP1 and DP2 on HCE cells indicated that if the % viability was below 70%, it has cytotoxicity potential. The marketed formulation (Xiidra) is lifitegrast ophthalmic solution 5% (Keating 2017; Li et al. 2022), i.e., is 50 mg/mL. The percentage degradation occurred in acidic hydrolytic study is greater than 20%. Consecutively, as a preliminary study, a concentration range of 5-300 µg/mL of both degradation products was used. At this concentration range, DP1 was observed to be non-cytotoxic to the cells, whereas DP2 exhibited significant toxicity towards the cells at higher concentrations (Figure S17). To understand the toxicity profile better, cell viability (Prajapati and Kothari 2022) was assessed with different concentration ranges for both DP1 and DP2 to study the effect of higher concentrations of DP1 and lower concentrations of DP2. Since the current study highlights and illustrates the cell viability upon treatment with the DPs, DMSO treatment is used as a negative control where minimum cell viability is expected. Regarding the vehicular control for DMSO, the amount of DMSO employed to dissolve the DP compounds in the cellular study was negligible and its influence was also checked by MTT assay and found no effect of DMSO at this concentration. Figure 3 shows that DP1 is relatively less cytotoxic than DP2. The cells were observed to be significantly affected by DP1 only at the highest concentration employed (1280 µg/mL) whereas in the case of DP2, the cell viability was found to significantly reduce from 8 µg/mL of comcentration. As a result, high concentrations of impurities must be controlled because human adverse events may occur.