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Synthesis of a first-generation l -rhamnose dendron
Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a first-generation L-rhamnose dendron Jérôme Alsarraf, Paul Gormand, Jean Legault, Mouadh Mihoub, André Pichette ⇑ Chaire de recherche sur les agents anticancéreux d’origine naturelle, Laboratoire d’analyse et de séparation des essences végétales (LASEVE), Département des Sciences Fondamentales, Université du Québec à Chicoutimi, 555, boulevard de l’Université, Chicoutimi (Québec) G7H 2B1, Canada
a r t i c l e
i n f o
Article history: Received 16 December 2019 Revised 30 January 2020 Accepted 3 February 2020 Available online xxxx Keywords: L-Rhamnose Glycodendrimer Multivalent interactions Anti-carbohydrate antibodies
a b s t r a c t During the last few years, various strategies for cancer therapy have emerged where L-rhamnose interacts with either an anti-rhamnose antibody or a hypothetically over-expressed L-rhamnose-binding lectin. These studies have led to promising results in cancer immunotherapy and the design of selective cytotoxic rhamnosides, respectively. We have synthesised an L-rhamnose dendron designed to amplify the interaction between L-rhamnose and multivalent receptors. The dendron was prepared in a very good 27% yield over 8 steps. It features an azide bearing side chain making it a versatile building block for the construction of innovative glycoconjugates relying on the peculiar properties of L-rhamnose for cancer treatment. Ó 2020 Elsevier Ltd. All rights reserved.
Introduction L-Rhamnose is a deoxy sugar that is common in plants and microorganisms but not found in mammalian glycans. As such, it is recognised as a xenoantigen by human anti-L-rhamnose antibodies. Anti-L-rhamnose antibodies rank among the most abundant anti-carbohydrate antibodies in human serum [1]. Consequently, L-rhamnose
emerged as a relevant candidate in cancer immunotherapy [2,3]. In this approach, a L-rhamnose conjugate is used to recruit endogenous anti-carbohydrate antibodies to malignant cells and induce an antitumor immune response [4]. Several L-rhamnosides were designed for this purpose and provided promising results in vitro and in vivo [5]. For instance, L-rhamnose
functionalized liposomes were shown to delay the tumour growth in 4T1 breast cancer bearing mice with minimal toxicity [6]. In this approach, the low-affinity multivalent interaction between carbohydrates and antibodies is responsible for the efficient recognition of cancer cells by the immune system [7,8]. Another therapeutic strategy based on the peculiar properties of consists of the incorporation of this monosaccharide onto the scaffold of cytotoxic agents. For instance, our group demonstrated that the betulinol 3,28-di-O-a-L-rhamnopyranoside was more active than the parent triterpene [9] with significant antitumor activity in vivo on Lewis lung carcinoma (LLC1) tumour-bearing mice [10]. In the same way, the betulinic acid 3-O-a-L-rhamnopyranoside displayed an appealing cytotoxicity,
along with a degree of selectivity for cancer cells [11]. The striking properties of L-rhamnose were also studied by other teams, leading to the biological evaluation of glycosides derived from various aglycones including anthracenes [12,13] and steroids [14]. The cytotoxicity of some L-rhamnose-bearing saponins was shown to match their internalisation within cancer cells [15]. The presence of a L-rhamnose-binding lectin [16] expressed at the surface of various malignant cell lines was proposed recently [17] and could explain the selective cytotoxicity of some rhamnosides. As both antibodies and lectins are multivalent receptors, we wondered if the impact of L-rhamnose could be amplified by a multivalent platform displaying several L-rhamnose moieties [18,19]. Various glycodendrimers were indeed shown to bind strongly with antibodies and lectins with affinities growing in a non-linear fashion in virtue of the so-called cluster effect [20]. Herein we report the synthesis of the first rhamnose dendron 1 (Fig. 1) designed to make the most of the interaction between L-rhamnose
and either a rhamnose-binding lectin or an anti-rhamnose antibody in various cancer treatment strategies.
L-rhamnose
⇑ Corresponding author. E-mail address: [email protected] (A. Pichette).
Results and discussion The multivalent device 1 was constructed around a gallic acid core that would accommodate three carbohydrate units on its phenol functions as well as an azide-bearing triethylene glycol linker anchored to its carboxylic acid. Designed as such, the glycocluster 1 could be readily conjugated to various alkyne bearing molecular constructs through its azide function relying on the ‘‘click chemistry” copper (I) catalysed 1,3-dipolar cycloaddition. This approach has already been implemented in the synthesis of
https://doi.org/10.1016/j.tetlet.2020.151706 0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: J. Alsarraf, P. Gormand, J. Legault et al., Synthesis of a first-generation L-rhamnose dendron, Tetrahedron Letters, https://doi.org/ 10.1016/j.tetlet.2020.151706
2
J. Alsarraf et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 2. Initial glycosylation attempt using peracetylated L-rhamnoside donor 5a. Fig. 1. Structure of the first-generation L-rhamnose dendron 1.
antibody-recruiting molecules [21]. The azide could also be reduced to the corresponding primary amine to enable its condensation onto electrophilic substrates following a straightforward sequence. The resulting glycoconjugates could then be involved in various anticancer strategies where its L-rhamnose cluster would interact strongly with the suitable multivalent receptor. The synthesis of 1 started from methyl gallate 2 (Scheme 1). Ethylene glycol chains were first incorporated on the phenol functionalities using bromoethyl acetate under basic conditions [22]. The acetates were then deprotected by transesterification to provide triol 4 that was ready to accommodate the three rhamnose molecules. Interestingly, this sequence could be adapted to oligoethylene glycol chains of various lengths. The space between the carbohydrate moieties and the flexibility of the dendritic core could therefore be tuned and optimised as these parameters were shown to be crucial for optimal polyvalent interactions [23]. Triol 4 was initially treated with 2,3,4-tri-O-acetyl-a-L-rhamnoside trichloroacetimidate 5a [24] in the presence of a catalytic amount of trimethylsilyl trifluoromethanesulfonate (TMSOTf) (Scheme 2). Unfortunately, these conditions failed to provide the expected conjugate 6a as it was only obtained as part of an inseparable complex mixture. The formation of undesired orthoesters [25] and poor stereoselectivity of the glycosylation reaction were suspected to be responsible for this disappointing result. As the nature of the ester protective group at the O-2 position of the glycosyl donor could affect the selectivity of the glycosylation reaction [26], we switched from the peracetylated L-rhamnoside donor 5a to its perbenzoylated counterpart 5b. Pleasingly, treatment of the triol 4 with a small excess of the 2,3,4-tri-O-benzoyla-L-rhamnoside donor 5b [11] in the presence of a catalytic amount of TMSOTf successfully afforded the glycosylation product 6b in a satisfying 71% yield after 1 h of agitation at room temperature (Scheme 3). The stereochemical outcome of the transformation was secured by the participation of the benzoate protective group on the C-2
Scheme 3. Synthesis of the rhamnose cluster 8. Reagents and conditions: i) TMSOTf, CH2Cl2, 0 °C to RT, 30 min (71%); ii) MeONa, MeOH, 0 °C, 30 min (93%); iii) KOH, EtOH/H2O, reflux, 1 h; iv) Ac2O, DMAP, pyridine, 0 °C to RT, 16 h (75%, 2 steps).
position of carbohydrates in the glycosylation mechanism [27]. The benzoates within intermediate 6b were then deprotected to afford methyl ester 7. At this stage, an undecoupled 13C NMR experiment was carried out to confirm the stereochemistry of the anomeric carbons (Fig. 2) [28]. Indeed, L-rhamnosides in 1C4 conformation feature an equatorial proton at the C-2 position. As a result, the dihedral angles between the anomeric and the C-2 C–H bonds are similar for a- and b-L-rhamnosides and the coupling constant of the anomeric proton cannot confirm the stereochemistry unambiguously. 168.0 Hz and 168.2 Hz coupling constants were measured between the anomeric protons and carbons at 101.9 and 101.7 ppm, respectively. These values are characteristic of a glycosidic bonds for L-rhamnose [29] confirming the intended anomeric stereochemistry. Methyl ester 7 was then hydrolysed and its carbohydrate units peracetylated using acetic anhydride and 4dimethylaminopyridine (DMAP) in pyridine to furnish the carboxylic acid 8 in 75% yield over two steps. The azide-bearing triethylene glycol side chain 9 was condensed on the carboxylic acid 8 under peptide coupling conditions (Scheme 4) affording the amide intermediate 10 in 86% yield. A final deprotection of the nine acetates on 10 provided the L-rhamnoside
Scheme 1. Construction of the dendritic core 4. Reagents and conditions: i) K2CO3, KI, DMF, 75 °C, 18 h; ii) MeONa, MeOH, 0 °C, 30 min (73%, 2 steps).
dendron 1 in an excellent 88% yield. Overall, the first-generation dendron 1 was obtained with an appealing 27% yield over 8 steps making it readily accessible from inexpensive methyl gallate.
Please cite this article as: J. Alsarraf, P. Gormand, J. Legault et al., Synthesis of a first-generation L-rhamnose dendron, Tetrahedron Letters, https://doi.org/ 10.1016/j.tetlet.2020.151706
J. Alsarraf et al. / Tetrahedron Letters xxx (xxxx) xxx
3
versatile building block for the construction of complex glycoconjugates. As several promising therapeutic strategies could take advantage of multivalent interactions between L-rhamnose and a suitable receptor (i.e. anti-rhamnose antibodies or rhamnosebinding lectins), it is believed that the dendron designed herein could be involved in the synthesis of novel anticancer drugs. Declaration of Competing 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. Acknowledgments The authors acknowledge the Chaire de recherche sur les agents anticancéreux d’origine naturelle for funding. This work was supported by the Canadian Institutes of Health Research (CIHR, operating grants 311906 and 326083 to A. P. and J. L.). Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.tetlet.2020.151706. References
Fig. 2. (a) Chemical shifts and 1JC–H coupling constants of the anomeric carbons of 7; (b) enlargement of the undecoupled 13C NMR spectrum of 7 in the area of the anomeric carbons.
Scheme 4. Incorporation of the azide-bearing side chain and final deprotection. Reagents and conditions: i) HBTU, DMF, RT, 1 h (86%); ii) MeONa, CH2Cl2/MeOH, 0 °C to RT, 1 h (88%).
Conclusion In summary, we have devised an efficient synthesis of the first L-rhamnose
cluster designed for multivalent interactions. The carbohydrate dendron 1 was obtained following a straightforward sequence in good yields. Its azide-bearing side chain makes it a
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Please cite this article as: J. Alsarraf, P. Gormand, J. Legault et al., Synthesis of a first-generation L-rhamnose dendron, Tetrahedron Letters, https://doi.org/ 10.1016/j.tetlet.2020.151706
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a first-generation L-rhamnose dendron Jérôme Alsarraf, Paul Gormand, Jean Legault, Mouadh Mihoub, André Pichette ⇑ Chaire de recherche sur les agents anticancéreux d’origine naturelle, Laboratoire d’analyse et de séparation des essences végétales (LASEVE), Département des Sciences Fondamentales, Université du Québec à Chicoutimi, 555, boulevard de l’Université, Chicoutimi (Québec) G7H 2B1, Canada
a r t i c l e
i n f o
Article history: Received 16 December 2019 Revised 30 January 2020 Accepted 3 February 2020 Available online xxxx Keywords: L-Rhamnose Glycodendrimer Multivalent interactions Anti-carbohydrate antibodies
a b s t r a c t During the last few years, various strategies for cancer therapy have emerged where L-rhamnose interacts with either an anti-rhamnose antibody or a hypothetically over-expressed L-rhamnose-binding lectin. These studies have led to promising results in cancer immunotherapy and the design of selective cytotoxic rhamnosides, respectively. We have synthesised an L-rhamnose dendron designed to amplify the interaction between L-rhamnose and multivalent receptors. The dendron was prepared in a very good 27% yield over 8 steps. It features an azide bearing side chain making it a versatile building block for the construction of innovative glycoconjugates relying on the peculiar properties of L-rhamnose for cancer treatment. Ó 2020 Elsevier Ltd. All rights reserved.
Introduction L-Rhamnose is a deoxy sugar that is common in plants and microorganisms but not found in mammalian glycans. As such, it is recognised as a xenoantigen by human anti-L-rhamnose antibodies. Anti-L-rhamnose antibodies rank among the most abundant anti-carbohydrate antibodies in human serum [1]. Consequently, L-rhamnose
emerged as a relevant candidate in cancer immunotherapy [2,3]. In this approach, a L-rhamnose conjugate is used to recruit endogenous anti-carbohydrate antibodies to malignant cells and induce an antitumor immune response [4]. Several L-rhamnosides were designed for this purpose and provided promising results in vitro and in vivo [5]. For instance, L-rhamnose
functionalized liposomes were shown to delay the tumour growth in 4T1 breast cancer bearing mice with minimal toxicity [6]. In this approach, the low-affinity multivalent interaction between carbohydrates and antibodies is responsible for the efficient recognition of cancer cells by the immune system [7,8]. Another therapeutic strategy based on the peculiar properties of consists of the incorporation of this monosaccharide onto the scaffold of cytotoxic agents. For instance, our group demonstrated that the betulinol 3,28-di-O-a-L-rhamnopyranoside was more active than the parent triterpene [9] with significant antitumor activity in vivo on Lewis lung carcinoma (LLC1) tumour-bearing mice [10]. In the same way, the betulinic acid 3-O-a-L-rhamnopyranoside displayed an appealing cytotoxicity,
along with a degree of selectivity for cancer cells [11]. The striking properties of L-rhamnose were also studied by other teams, leading to the biological evaluation of glycosides derived from various aglycones including anthracenes [12,13] and steroids [14]. The cytotoxicity of some L-rhamnose-bearing saponins was shown to match their internalisation within cancer cells [15]. The presence of a L-rhamnose-binding lectin [16] expressed at the surface of various malignant cell lines was proposed recently [17] and could explain the selective cytotoxicity of some rhamnosides. As both antibodies and lectins are multivalent receptors, we wondered if the impact of L-rhamnose could be amplified by a multivalent platform displaying several L-rhamnose moieties [18,19]. Various glycodendrimers were indeed shown to bind strongly with antibodies and lectins with affinities growing in a non-linear fashion in virtue of the so-called cluster effect [20]. Herein we report the synthesis of the first rhamnose dendron 1 (Fig. 1) designed to make the most of the interaction between L-rhamnose
and either a rhamnose-binding lectin or an anti-rhamnose antibody in various cancer treatment strategies.
L-rhamnose
⇑ Corresponding author. E-mail address: [email protected] (A. Pichette).
Results and discussion The multivalent device 1 was constructed around a gallic acid core that would accommodate three carbohydrate units on its phenol functions as well as an azide-bearing triethylene glycol linker anchored to its carboxylic acid. Designed as such, the glycocluster 1 could be readily conjugated to various alkyne bearing molecular constructs through its azide function relying on the ‘‘click chemistry” copper (I) catalysed 1,3-dipolar cycloaddition. This approach has already been implemented in the synthesis of
https://doi.org/10.1016/j.tetlet.2020.151706 0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: J. Alsarraf, P. Gormand, J. Legault et al., Synthesis of a first-generation L-rhamnose dendron, Tetrahedron Letters, https://doi.org/ 10.1016/j.tetlet.2020.151706
2
J. Alsarraf et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 2. Initial glycosylation attempt using peracetylated L-rhamnoside donor 5a. Fig. 1. Structure of the first-generation L-rhamnose dendron 1.
antibody-recruiting molecules [21]. The azide could also be reduced to the corresponding primary amine to enable its condensation onto electrophilic substrates following a straightforward sequence. The resulting glycoconjugates could then be involved in various anticancer strategies where its L-rhamnose cluster would interact strongly with the suitable multivalent receptor. The synthesis of 1 started from methyl gallate 2 (Scheme 1). Ethylene glycol chains were first incorporated on the phenol functionalities using bromoethyl acetate under basic conditions [22]. The acetates were then deprotected by transesterification to provide triol 4 that was ready to accommodate the three rhamnose molecules. Interestingly, this sequence could be adapted to oligoethylene glycol chains of various lengths. The space between the carbohydrate moieties and the flexibility of the dendritic core could therefore be tuned and optimised as these parameters were shown to be crucial for optimal polyvalent interactions [23]. Triol 4 was initially treated with 2,3,4-tri-O-acetyl-a-L-rhamnoside trichloroacetimidate 5a [24] in the presence of a catalytic amount of trimethylsilyl trifluoromethanesulfonate (TMSOTf) (Scheme 2). Unfortunately, these conditions failed to provide the expected conjugate 6a as it was only obtained as part of an inseparable complex mixture. The formation of undesired orthoesters [25] and poor stereoselectivity of the glycosylation reaction were suspected to be responsible for this disappointing result. As the nature of the ester protective group at the O-2 position of the glycosyl donor could affect the selectivity of the glycosylation reaction [26], we switched from the peracetylated L-rhamnoside donor 5a to its perbenzoylated counterpart 5b. Pleasingly, treatment of the triol 4 with a small excess of the 2,3,4-tri-O-benzoyla-L-rhamnoside donor 5b [11] in the presence of a catalytic amount of TMSOTf successfully afforded the glycosylation product 6b in a satisfying 71% yield after 1 h of agitation at room temperature (Scheme 3). The stereochemical outcome of the transformation was secured by the participation of the benzoate protective group on the C-2
Scheme 3. Synthesis of the rhamnose cluster 8. Reagents and conditions: i) TMSOTf, CH2Cl2, 0 °C to RT, 30 min (71%); ii) MeONa, MeOH, 0 °C, 30 min (93%); iii) KOH, EtOH/H2O, reflux, 1 h; iv) Ac2O, DMAP, pyridine, 0 °C to RT, 16 h (75%, 2 steps).
position of carbohydrates in the glycosylation mechanism [27]. The benzoates within intermediate 6b were then deprotected to afford methyl ester 7. At this stage, an undecoupled 13C NMR experiment was carried out to confirm the stereochemistry of the anomeric carbons (Fig. 2) [28]. Indeed, L-rhamnosides in 1C4 conformation feature an equatorial proton at the C-2 position. As a result, the dihedral angles between the anomeric and the C-2 C–H bonds are similar for a- and b-L-rhamnosides and the coupling constant of the anomeric proton cannot confirm the stereochemistry unambiguously. 168.0 Hz and 168.2 Hz coupling constants were measured between the anomeric protons and carbons at 101.9 and 101.7 ppm, respectively. These values are characteristic of a glycosidic bonds for L-rhamnose [29] confirming the intended anomeric stereochemistry. Methyl ester 7 was then hydrolysed and its carbohydrate units peracetylated using acetic anhydride and 4dimethylaminopyridine (DMAP) in pyridine to furnish the carboxylic acid 8 in 75% yield over two steps. The azide-bearing triethylene glycol side chain 9 was condensed on the carboxylic acid 8 under peptide coupling conditions (Scheme 4) affording the amide intermediate 10 in 86% yield. A final deprotection of the nine acetates on 10 provided the L-rhamnoside
Scheme 1. Construction of the dendritic core 4. Reagents and conditions: i) K2CO3, KI, DMF, 75 °C, 18 h; ii) MeONa, MeOH, 0 °C, 30 min (73%, 2 steps).
dendron 1 in an excellent 88% yield. Overall, the first-generation dendron 1 was obtained with an appealing 27% yield over 8 steps making it readily accessible from inexpensive methyl gallate.
Please cite this article as: J. Alsarraf, P. Gormand, J. Legault et al., Synthesis of a first-generation L-rhamnose dendron, Tetrahedron Letters, https://doi.org/ 10.1016/j.tetlet.2020.151706
J. Alsarraf et al. / Tetrahedron Letters xxx (xxxx) xxx
3
versatile building block for the construction of complex glycoconjugates. As several promising therapeutic strategies could take advantage of multivalent interactions between L-rhamnose and a suitable receptor (i.e. anti-rhamnose antibodies or rhamnosebinding lectins), it is believed that the dendron designed herein could be involved in the synthesis of novel anticancer drugs. Declaration of Competing 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. Acknowledgments The authors acknowledge the Chaire de recherche sur les agents anticancéreux d’origine naturelle for funding. This work was supported by the Canadian Institutes of Health Research (CIHR, operating grants 311906 and 326083 to A. P. and J. L.). Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.tetlet.2020.151706. References
Fig. 2. (a) Chemical shifts and 1JC–H coupling constants of the anomeric carbons of 7; (b) enlargement of the undecoupled 13C NMR spectrum of 7 in the area of the anomeric carbons.
Scheme 4. Incorporation of the azide-bearing side chain and final deprotection. Reagents and conditions: i) HBTU, DMF, RT, 1 h (86%); ii) MeONa, CH2Cl2/MeOH, 0 °C to RT, 1 h (88%).
Conclusion In summary, we have devised an efficient synthesis of the first L-rhamnose
cluster designed for multivalent interactions. The carbohydrate dendron 1 was obtained following a straightforward sequence in good yields. Its azide-bearing side chain makes it a
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Please cite this article as: J. Alsarraf, P. Gormand, J. Legault et al., Synthesis of a first-generation L-rhamnose dendron, Tetrahedron Letters, https://doi.org/ 10.1016/j.tetlet.2020.151706