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Novel glycosyl prodrug of RXP03 as MMP-11 prodrug: design, synthesis and virtual screening


Like most phosphinic acids, the potent and selective RXP03 inhibitor of different MMPs exhibited moderate absorption and low bioavailability, which impaired its use. In an unprecedented attempt, we present an interesting synthetic approach to a new class of phosphinate prodrug, glycosyl ester of RXP03, to provide a potentially improved blood–brain barrier (BBB) behavior compared to the former lead compound RXP03. To validate this speculation, a predictive study for permeability enhancer of glycosyl ester of RXP03 showed encouraging insights to improve drug delivery across biological barriers.

Peer Review reports


There is growing evidence that matrix metalloproteases (MMPs) are potential targets for cancer therapy [1, 2]. It has been found that stromelysin-3 (MMP-11), a member of the MMP family that acts as a survival factor on cancer cells rather than as an inducer of cancer cell proliferation, is mainly involved in the formation of tumors rather than the growth of them [3,4,5]. The phosphinic peptide RXP03 (Fig. 1), which contains an unusually long side chain at P1’, was highly effective against various matrix metalloproteinases [6,7,8,9].

Fig. 1
figure 1

RXP03 is an effective inhibitor of (MMPs)

Unfortunately, this compound’s low lipophilicity and poor membrane permeability have prevented clinical application. A prodrug approach is proposed to achieve this goal by improving its absorption properties. The prodrug approach can mask the ionizable hydroxyl group in RXP03 to increase its lipophilicity and decrease salt formation. After absorption and enzymatic hydrolysis, the prodrug could release the active drug into the cells [10].

Choosing an attached core to incorporate into this type of prodrug was conceptually appealing as a starting point for the design [11,12,13]. Even though many compounds have interesting biological activities, a literature review prompted us to think that conjugating drugs with sugar units, especially glucose, might be an interesting aspect of the prodrug/derivatization approach. Several conjugates are more effective than their parent drugs at drug delivery [14,15,16]. As another feature of the attachment of sugar, glucose might facilitate transport pathways across multiple biological barriers [11,12,13]. As a result, sugar conjugation is capable of (i) using active transport systems, (ii) modifying the construct’s physical properties, and (iii) transporting to a specific target [11,12,13]. Notably, the absorption of β-linked sugar-drug conjugates is significantly higher than the a-anomers, which was the main reason for choosing 1,2,3,4-tetra-O-acetyl-β-d-glucopyranose (TGA) as the sugar component linked with RXP03 [17]. Glucose byproducts from the cleavage would not be toxic, and the resultant drug would not be stereogenic to phosphorus. Interestingly, several phosphinate esters have been developed and used in clinical trials (Fig. 2) [18,19,20,21,22,23], but never sugar-based esters as proposed here.

Fig. 2
figure 2

Phosphinic acid prodrugs and drugs with potential clinical use

Recently we have been interested in enhancing the esterification reaction of phosphinic acids. In the light of these findings and continuation of our prior work on the synthesis of highly selective inhibitors of MMP-11, such as RXP03 [24, 25], we reported the design and synthesis of a novel class of phosphinate prodrug derived from glycosyl ester (Glycosyl prodrug of RXP03 according to our esterification method [26] with the vision of improving the penetration of the BBB, followed by studying the tissue distribution of both parent-drug RXP03 and its prodrug, in particular, crossing the BBB using molecular docking studies.

Results and discussion


The diastereoselective synthetic protocol presented in Scheme 1 allows the synthesis of the two diastereoisomers of RXP03 in gram scale and high yields using our previously reported synthesis protocol (Scheme 1) [24]. The required ethyl 2-methylene-5-phenylpentanoate 2 was synthesized by alkylation of triethyl phosphonoacetate 1 with 1-bromo-3-phenylpropane followed by a Horner–Wadsworth–Emmons (HWE) condensation with formaldehyde. Michael-type addition of acrylate 2 to (R)-Z-PhePO2H2 (R)-3 by activation with HMDS leads to the phosphinic dipeptide 4. Saponification of the ethyl ester of 4 produced 5. Coupling with (S)-TrpNH2 6 provided the phosphinic pseudo tripeptide (R, S/R, S)-7 as mixture of pairs of isomers with different solubility properties. When (R,S,S/R,R,S)-7 was treated with absolute ethanol, a solid precipitated, which proved to be isomer (R, S, S)-7, while the filtrate consisted exclusively of isomer (R, R, S)-7. Finally, the purity and assignment of the absolute configuration of the target isomer (R, S, S)-7 were performed according to methods described in detail previously using RP-HPLC [24].

Scheme 1
scheme 1

The synthetic pathway used to prepare (R, S, S)-7 and the resolution of its diastereomers

The prodrug 9 was prepared following our previous procedure [26] via the phosphinic chloride, which was generated by treatment of the phosphinic acid RXP03 with thionyl chloride in anhydrous diethyl ether; the phosphinic chloride was then reacted in situ with 1,2,3,4-tetra-O-acetyl-β-d-glucopyranose 8 in the presence of a catalytic amount of triethylamine to give the desired glycosyl prodrug 9, as shown in Scheme 2.

Scheme 2
scheme 2

Synthesis of target glycosyl prodrug 9

Virtual screening

The docking energies, ligand efficiency (LE) values, and the list of the contacting amino acid residues are summarized in Tables 1, 2, 3. As can be seen, the docking energies within the glycosylated-unglycosylated pairs of molecules hardly differ, which is not feasible regarding the huge structural difference within each pair. This is the consequence of the additive energy calculation method of the docking programs. To scale down this additivity, different ligand efficiency values are used; here, the docking energy was divided by the number of non-hydrogen atoms of the ligand [27]. As a consensus, higher than − 0.24 a ligand is considered a weak binder or non-binder. The comparative interaction patterns for this series of ligands are shown in Tables 1, 2, 3. For comparison, the putative binders apatinib and (−)-epigallocatechin-3-gallate (EGCG) were also involved in the docking calculations.

Table 1 The free energy estimates and molecular docking interactions of investigated compounds towards Claudin-4
Table 2 The free energy estimates and molecular docking interactions of investigated compounds towards Claudin-15
Table 3 The free energy estimates and molecular docking interactions of investigated compounds towards Claudin-19

Role of glucose component

Glucose derivatives generally bind to claudins with lower docking energies, i.e., stronger binders with some exceptions, the RRR, SRR, and SSS compound docked to claudins 15 and 19. However, the difference is always small (Tables 1, 2, 3). In contrast, by the LE values, the unglycosylated compounds were unambiguously stronger binders than the corresponding glycosylated derivatives (Tables 1, 2, 3). The only case when the glycosylated derivative could be considered as a binder, showing the threshold LE value, is the compound with RSR configuration at claudin-15.

Role of the chirality of phosphorous

The chirality has no direct effect on the LE values. Thus, no conclusion can be drawn for binding preference. It should be noted, however, that these molecules all have enough flexibility to compensate for some unfeasible chirality, probably because none of them can be considered a strong binder (Tables 1, 2, 3).

Multivariate analysis of the residue-level interaction pattern

Instead of counting different interactions (polar, hydrophobic etc.) to compare, the full interaction patterns of the docked ligands were used for comparison. Although the current approach does not involve either chemical information about the type of the interactions like hydrogen bonding, aromatic-aromatic etc. or physical like attractive or repulsive, it holds information about the full list of the sites the interactions appeared at. This is presented as lists of the specific interacting residues of the protein in a tabular form inputted to MCA which can be seen in Tables 1, 2, 3. Multivariate statistics is a descriptive tool which can interpret this kind of data. The results are shown in biplots of the factor maps, which show relations between the interacting protein residues and the binding ligands (Figs. 3, 4, 5). Additionally, as a supplementary quantitative variable (not involved in the MCA analysis), the LE values were mapped onto the factor maps to add a direction for the energetically preferred residues and ligands within this series of ligands. The opposite direction of the LE values (deeper interaction energy) points to stronger binding.

Fig. 3
figure 3

Biplot (left) of the interaction patterns and projection of the ligand efficiency on the factor map for claudin-4 (right). Interacting residues of the compounds are shown in red and blue, respectively

Fig. 4
figure 4

Biplot (left) of the interaction patterns and projection of the ligand efficiency on the factor map for claudin-15 (right). Interacting residues of the compounds are shown in red and blue, respectively

Fig. 5
figure 5

Biplot (left) of the interaction patterns and projection of the ligand efficiency on the factor map for claudin-19 (right). Interacting residues of the compounds are shown in red and blue, respectively

Although the factor maps do not show the separation of the ligands as binders or non-binders, it is notable that the opposite direction of the LE vector always points toward the stronger binders. However, accepting the binder/non-binder threshold value, the estimated values for the sugar-conjugated derivatives suggest that they are non-binders. Thus, an estimated interaction pattern could be meaningless. Based on these observations, the non-conjugated compounds could bind all three human claudins investigated, while the conjugated compounds would not. The only candidate can be the RXP03_RSR_gluc_Ac at claudin-15. The docked poses of the RSR compounds pair to claudin-15 (Fig. 6). Some of the interacting residues in the proximity of RXP03_RSR and RXP03_RSR_gluc_Ac on the biplot are also shown.

Fig. 6
figure 6

Docked poses of RXP03_RSR_gluc_(magenta) and Ac and RXP03_RSR (cyan) on human claudin-15. Interacting residues are shown in green

Experimental section

Detailed experimental procedures

figure a

Ethyl-2-methylene-5-phenylpentanoate (2) [28]

A solution of t-BuOK (841 mg, 7.5 mmol) in dry DMF (25 ml) was added (C2H5O)2P(O)CH2CO2C2H5 1 (1 ml, 5 mmol) slowly and the reaction mixture (RXM) was allowed to stir for 10 min at 10 0 °C under Ar. The C6H5(CH2)3Br (1.14 ml, 7.5 mmol) was added slowly into the flask, and the RXM was allowed to stir for 3 h at 85 °C under Ar. Then K2CO3 (2 g, 15 mmol) and paraformaldehyde (450 mg, 15 mmol) were added, and the resulting RXM was kept at reflux for 6 h. After completion, 0.5 M HCl was used to quench the reaction to pH ~ 5, and the RXM was extracted twice with Et2O. Drying the organic phase with MgSO4, then filtering and evaporating it under reduced pressure to afford pure 2 after purification of the residue by column chromatography (PE/AcOEt, v/v, 3/2) as a colorless oil (654 mg, 60%); 1H NMR (400 MHz, CDCl3) δ 1.29 (t, J = 7.12 Hz, 3H), 1.77–1.85 (m, 2H), 2.35 (m, 2H), 2.64 (m, 2H), 4.21 (q, J = 7.13 Hz, 2H), 5.52 (s, 1H), 6.15 (s, 1H), 7.16–7.19 (m, 3H), 7.24–7.29 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.38, 30.10, 31.59, 35.43, 60.60, 124.48, 125.87, 128.43, 140.70, 142.15, 167.41.

figure b

(R, R/S)-2-[(1-Benzyloxycarbonylamino-2-phenyl–ethyl)-hydroxy-phosphinoyl methyl]-5-phenyl pentanoic acid ethyl ester (4) [24]

A mixture of the phosphinic acid (R)-3 (1.6 g, 5 mmol) and HMDS (5.3 ml, 25 mmol) was flushed with Ar and heated at 110 °C for 3 h. A dropwise addition of 2 (1.42 g, 6.5 mmol) was performed for 30 min, followed by stirring for 4 h. Once the RXM had cooled to 70 °C, absolute EtOH (6 ml) was added dropwise and stirred for 30 min at RT. Following concentration, the residue was dissolved in AcOEt, washed with 2 M HCl, brine, and dried over anhydrous Na2SO4, and the crude product was obtained after solvent evaporation. Flash chromatography using (DCM/MeOH/AcOH, v/v, 7/0.3/0.3) as eluent provided the title product 4 as a white solid (2.4 g, 90%). 1H NMR (400 MHz, CDCl3) δ 1.19–1.30 (m, 3H), 1.43–1.57 (m, 4H), 1.61–1.81 (m, 1H), 2.13–2.37 (m, 1H), 2.51–2.63 (m, 2H), 2.72–2.99 (m, 2H), 3.21–3.36 (m, 1H), 4.20–4.40 (m, 3H), 4.98 (s, 2H), 5.50–5.69 (m, 1H), 7.10–7.36 (m, 15H); 13C NMR (100 MHz, CDCl3) δ 14.21, 28.48, 28.66, 34.50, 35.10, 36.13, 39.49, 52.35, 67.84, 67.99, 126.21, 127.32, 127.88, 128.51, 128.88, 128.93, 129.10, 129.43, 129.67, 136.23, 136.54, 141.92, 156.25, 176.77; 31P NMR (162 MHz, CDCl3) δ 52.88, 53.76.

figure c

(R,R/S)-2-[(1-Benzyloxycarbonylamino-2-phenyl–ethyl)-hydroxy-phosphinoyl methyl]-5-phenyl-pentanoic acid (5) [24]

1 M NaOH(aq) (100 ml) was added dropwise to a stirred solution of compound 4 (3.5 g, 6.5 mmol) in EtOH (100 ml). The RXM was allowed to stir for 24 h at RT. After removing the solvent, the residue was diluted with H2O, acidified with 3 M HCl in ice water to pH = 1, filtered, and washed with H2O. (3 × 10 ml), and Et2O (10 ml) and dried over P2O5 overnight afforded 5 as a white solid (3.1 g, 93%). 1H NMR (400 MHz, CDCl3) δ 1.44–1.56 (m, 4H), 1.65–1.88 (m, 1H), 2.13–2.30 (m, 1H), 2.52–2.66 (m, 2H), 2.87–2.88 (m, 2H), 3.11–3.37 (m, 1H), 4.25–4.39 (m, 1H), 4.98 (s, 2H), 5.38–5.63 (m, 1H), 7.12–7.29 (m, 15H); 13C NMR (100 MHz, CDCl3) δ 28.12, 28.90, 33.31, 34.21, 35.53, 38.59, 51.32, 68.21, 126.39, 127.52, 127.93, 128.49, 128.56, 128.79, 128.96, 129.27, 129.81, 136.40, 136.92, 141.92, 157.73, 181.55; 31P NMR (162 MHz, CDCl3) δ 51.65, 53.13.

figure d

(R, R/S, S)(1-Benzyloxycarbonylamino-2-phenyl–ethyl)-{2-[1-carbamoyl-2-(1H-indol-3-yl)-ethylcarbamoyl]-5-phenyl-pentyl}phosphinic acid ((R, R/S, S)-7) [24]

To a chilled solution of 5 (2 g, 4 mmol) in DCM (90 ml) containing DIPEA (0.68 ml, 4 mmol), a solution of S-tryptophan amide 6 (0.8 g, 40 mmol), HOBt (0.52 g, 4 mmol), EDC.HCl (3.1 g, 16 mmol) and DIPEA (0.68 ml, 4 mmol) were added, and the RXM was allowed to stir for 30 min at 0 °C and then at RT overnight. After being finished, the RXM was diluted with DCM (200 ml), washed with a solution of 1 M HCl (2 × 10 ml), a saturated solution of NH4HCO3 (3 × 10 ml), 1 M HCl to pH = 1, and brine (30 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified over silica gel chromatography using (DCM/MeOH/AcOH, v/v, 7/0.8/0.5) as eluent yielding (R, R/S, S)-7 as a white solid (2 g, 72%).

figure e

(R, S, S)(1-Benzyloxycarbonyl amino-2-phenyl–ethyl)-{2-[1-carbamoyl-2-(1H-indol-3-yl)-ethyl carbamoyl]-5-phenyl-pentyl}phosphinic acid ((R, S, S)-7) [24]

A stirred solution of (R,R/S,S)-7 (2 g, 2.87 mmol) in EtOH (50 ml) was refluxed for 30 min and then left at 4 °C overnight. After 18 h at this temperature, the white solid precipitate was filtered and washed with cold absolute EtOH and dried over P2O5 to give (R,S,S)-7 (1.65 g, 83%). 1H NMR (400 MHz, DMSO-d6) δ 1.21–1.57 (m, 4H), 1.62–1.76 (m, 1H), 1.92–2.07 (m, 1H), 2.29–2.47 (m, 2H), 2.58–2.78 (m, 2H), 2.97–3.15 (m, 2H), 3.16–3.27 (m, 1H), 3.81–3.97 (m, 1H), 4.35–4.47 (d, 1H), 4.79–5.00 (m, 2H), 6.88–7.37 (m, 18H), 7.57–7.74 (m, 3H), 7.99 (d, 1H), 10.81 (s, 1H); 13C-NMR (100 MHz, DMSO-d6) δ 27.57, 28.54, 28.82, 29.43, 33.33, 34.15, 35.52, 52.58, 53.61, 54.15, 65.71, 111.22, 111.78, 118.61, 125.99, 127.40, 127.83, 127.97, 128.61, 128.61, 128.71, 129.42, 136.55, 137.69, 142.52, 156.34, 174.01, 174.12; 31P-NMR (162 MHz, DMSO-d6) δ 44.88, 44.15. HRMS (ESI/QTOF) m/z: [M+H]+ Calcd for C39H43N4O6PH 695.2998; Found 695.2988.

figure f

(2S,3R,4S,5R,6S)-6-(((((R)-2-(((S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl)carbamoyl)-5-phenylpentyl)((R)-1-(((benzyloxy)carbonyl)amino)-2-phenyl ethyl)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-betrayal tetraacetate (9)

Thionyl chloride (0.36 g, 3 mmol) was added dropwise to the solution of (R, S, S)-7 (0.83 g, 1.2 mmol) in Et2O (5 ml) and 0.5 ml of DMF under nitrogen at 0 °C. The RXM was stirred at RT for 1.5 h and then concentrated. This resulting solid (0.80 g) dissolved in 7 ml of toluene, and the resulting solution was added dropwise to the mixture of 8 (0.42 g, 1.2 mmol) and TEA (0.2 ml, 1.43 mmol) in 5 ml of toluene at 0 °C. The RXM was refluxed for 9 h (monitored with 31P NMR), and then the triethylamine hydrochloride was removed by filtration. The filtrate was dried under vacuum, dissolved in Et2O and washed with a saturated solution of NaHCO3 and brine. The organic phase was dried over MgSO4 and filtered. The filtrate was concentrated and then treated with Et2O/hexane (1/1) at 0 °C, the white solid precipitate was filtered off and dried to give phosphinate 9 (0.94 g, 77%); 1H NMR (400 MHz, DMSO-d6) δ 1.19–1.42 (m, 4H), 1.60–1.72 (m, 1H), 1.86 (s, 3H),1.97–2.07 (m, 1H), 2.13 (s, 3H), 2.21 (s, 3H), 2.32 (s, 3H), 2.49–2.57 (m, 2H), 2.71–2.88 (m, 2H), 2.96–3.11 (m, 2H), 3.26–3.35 (m, 1H), 3.49–3.67 (m, 2H), 3.83–4.00 (m, 1H), 4.36–4.49 (d, 1H), 4.74–5.01 (m, 2H), 5.13 (m, 2H), 5.30–5.51 (t, 1H), 5.79–5.91 (d, 1H), 6.91–7.32 (m, 18H), 7.51–7.70 (m, 3H), 7.80–7.90 (d, 1H), 10.68 (s, 1H);13C-NMR (100 MHz, DMSO-d6) δ 21.11, 21.32, 21.44, 21.69, 27.23, 28.45, 28.34, 30.35, 33.01, 34.25, 35.61, 53.16, 54.34, 54.98, 60.25, 64.88, 68.12, 70.38, 72.67, 75.55, 91.51, 111.79, 111.89, 119.62, 125.03, 128.20, 128.33, 128.54, 128.61, 128.73, 128.89, 129.32, 136.11, 137.21, 143.50, 157.34, 168.13, 168.45, 168.65, 170.11, 174.36, 174.88; 31P-NMR (162 MHz, DMSO-d6) δ 49.01, 49.95. HRMS (MALDI) m/z: [M]+ Calcd for C53H61N4O15P 1024.3871; Found 1024.3858.

Virtual screening

Molecular docking

Docking calculations were performed to the available crystal structure of human claudin-4 (PDB code 5B2G, chain C), and the homology models of human claudin-15 and claudin-19 based on the corresponding mouse crystal structures (PDB codes and protein chains used were 4P79, chain A and 3X29, chain A, respectively). The docking program PLANTS [29] was chosen due to its built-in chemical capabilities. PSOVina [30] was used to rescore the docking energies of the docked poses obtained by PLANTS. PSOVina calculated the docking energies in kcal/mol, also the ligand efficiency values [27] and listed the interacting receptor atoms and residues. The centre of the docking sphere (the search space) was set to the centre of the putative interacting surface of ECL1 for each claudin protein. The docking method was similar to [31], i.e. the efficiency of the stochastic search was improved by repeating the calculations five times [32], and the docking with the lowest energy was regarded as the final result. Furthermore, the size of the docking sphere was calculated for each ligand individually in the program SPORE [29] based on the idea in [33]. However, the size of the docking shere was increased by 5 angstroms due to the uncertainness of the optimal centre and to allow the ligands more freedom to find the best fit.

Preparation of the ligands

The 3D structures of the ligands were drawn by the molecular structure editor program Avogadro [34]. The structures of apatibin and EGCG were downloaded from PubChem for further use. The protonation state of the molecules was set to pH 7.4, and then the structures were energy minimized using the MMFF94s molecular force field and conjugate gradient method. The minimization was terminated at 10–10 kcal/mol energy gradient.

Preparation of the protein structures

Residues missing in the crystal structures of human claudins were reconstructed by the homology modelling program MODELLER v10.2 [35], leaving the crystal structure's atomic coordinates unchanged. The 3D structure of human claudins 15 and 19 was prepared by MODELLER using the corresponding mouse crystal structures (PDB codes and protein chains used were 4P79, chain A, and 3X29, chain A, respectively. The human claudin 15 and 19 amino acid sequences were downloaded from Uniprot with accession codes P56746 and Q8N6F1, respectively.

Comparison of the interaction patterns of the docking poses by multivariate statistics

Docking results were evaluated by calculating docking energies and the poses the contacting receptor atoms characterized. The latter, a list of amino acid residues for each ligand, was compared by multiple correspondence analysis (MCA) using the R programming environment [36, 37]. The lists of the residues contacting the ligands were summarized. Each docking pose was characterized by a binary vector showing which residue in the list was involved in the interaction. These binary vectors, as interaction patterns, were used by MCA to compare the compounds. The biplots visualized the results in the factor maps showing the compounds belonging to the specific interactions. A molecular graphic was prepared by the molecular visualizer program Chimera v. 1.15 [38].


Quite often, esters can enhance the absorption and oral drug delivery of parent drugs. Considering these, various known drugs in clinical trials were discovered using esterification, such as sultamicillin, benorilate, and phosphinic inhibitor of ACE fosinoprilat. To find a novel MMP-11 prodrug, a novel phosphinate was developed by modifying the RXP03 structure to synthesize a novel compound, RXP03-sugar ester. Based on the docking results, none of the structural features alone could be a main driving force of stronger binding to the claudins investigated. Overall, the glucose derivatives would bind to claudins less preferably than their parent compounds and, regarding the mainly hydrophobic nature of the ECL1 of claudins (Figs. 3, 4, 5), it happens instead through hydrophobic interactions. A minor decrease caused by the glucose moiety was observed in the case of Claudine 19. It may be concluded that claudin 19 can bind the glucose derivatives with almost the same strength as the parent compound, while claudins 4 and 15 bind it significantly weaker. Due to the importance of RXP03-sugar esters, the stability of the prodrug in simulated gastric, intestinal, and plasma fluid, its solubility in vitro, and PAMPA-BBB studies will also be investigated and reported separately.

Data availability

All data generated or analysed during this study are included in this published article.


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The authors are greatly thankful to the Egyptian Petroleum Research Institute (EPRI) for research facilities.


Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB).

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MMA and MM played key roles in conceptualizing the project, providing oversight, conducting investigations, defining the methodology, creating visualizations, crafting the original draft of the writing, and participating in the review and editing process. DD made significant contributions to the project’s supervision. FÖ took the lead in commencing the formal data analysis and establishing the methodology for molecular docking. All authors collaborated in the creation of the original draft of the manuscript and collectively endorsed its final version.

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Correspondence to Moaz M. Abdou.

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Abdou, M.M., Ötvös, F., Dong, D. et al. Novel glycosyl prodrug of RXP03 as MMP-11 prodrug: design, synthesis and virtual screening. BMC Chemistry 17, 167 (2023).

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