Multigram Scale Synthesis of A21, A New Antibiotic Equally Effective

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Multigram Scale Synthesis of A21, a New Antibiotic Equally Effective and less Toxic Than Amphotericin B. José David Flores-Romero, Josué Rodríguez-Lozada, Manuel López-Ortiz, Ricardo Magaña, Iván Ortega-Blake, Ignacio Regla, and Mario Fernandez-Zertuche Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00211 • Publication Date (Web): 19 Jul 2016 Downloaded from http://pubs.acs.org on July 19, 2016

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Organic Process Research & Development

Multigram Scale Synthesis of A21, a New Antibiotic Equally Effective and less Toxic Than Amphotericin B. José David Flores-Romero,1 Josué Rodríguez-Lozada1, Manuel López-Ortiz2, Ricardo Magaña2, Iván Ortega-Blake3, Ignacio Regla2*and Mario Fernández-Zertuche1*, 1

Instituto de Investigación en Ciencias Básicas y Aplicadas, Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos 2

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Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México

Instituto de Ciencias Físicas, Universidad Nacional Autónoma de México

ACS Paragon Plus Environment

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Table of Contents Graphic


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KEYWORDS. Amphotericin B, derivatives, amide coupling, antifungal agents, macrolides

ABSTRACT A21 (2), is a new polyene macrolide Amphotericin B amide antibiotic derived from amphotericin B AmB (1), which has been tested extensively on pre-clinical trials showing the same antimycotic effectiveness and increased margin of safety over AmB (1). We present the multigram scale synthesis, isolation, purity assessment by HPLC and key aspects of its characterization by NMR studies of A21 (2).


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INTRODUCTION. Amphotericin B, AmB (1) (Figure 1) has been the most effective agent against systemic fungal infections (SFI) for over 60 years1, and recently its use has been extended to treat parasitic infections like leishmaniases.2 This antifungal agent belongs to the macrocyclic drug family known as polyene macrolides, which also includes amphotericin A, natamycin and nystatine; their chemical structures comprise a macrocyclic lactone ring, a polyene chain, multiple hydroxyl groups and an amino glycoside moiety.3

Figure 1. Structure of AmB (1). The use of polyene macrolides in medical practice, and of 1 in particular has been widely established. However, its clinical use has serious limitations due to the adverse effects that occur after his administration; mainly damage to kidney (nephrotoxicity)4 damage to the liver (hepatotoxicity)5 and anemia,6 by breaking the red blood cells. When these problems arise on patients under treatment with 1, it is necessary to suspend the treatment. Nevertheless, the lack of an effective alternative treatment for SFI has settled the clinical importance of 1 unchanged.7 During the last decade a large amount of research has been devoted to the understanding of the mechanism of action. It is widely accepted that 1 associates with membrane sterols to form barrel-stave ionic pores, which increases membrane permeability and modifies its potentials,


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leading to K+ ions leaking and cell death as a final step.8 In recent years, this mechanism of action has been questioned by the evidence of high biological activity of synthetically modified 1 molecules suggesting that ionic pore formation could be a secondary mechanism and that 1 works as a “sterol sponge”, extracting ergosterol from the fungal membrane and leading to cell death.9 Understanding the mechanism of action of 1 as an antibiotic, opens the possibility to carry out chemical modifications on its structure in order to reduce its toxicity, maintaining at the same time its maximum activity as antibiotic. Numerous attempts have been reported in the literature to modifiy the structure of 1 in order to reduce its toxicity. These include modification of the polyene chain;10 derivatization of the amino group on the mycosamine ring system;11 preparation of amides at the carboxylic function;12 removal of the exocyclic carboxylic function;13 synthesis of fluorinated derivatives14 and covalent dimers with carbonyl-amine linkage.15 More recently, elegant methodologies have been developed to remove the OH group at C-316 or at C-35.17 Our research group has made numerous attempts to modify the chemical structure of 1. As a result, we have found that through the preparation of several amide type derivatives, it is possible to develop a new antibiotic with these characteristics. Specifically, we found that an amide derivative prepared by the coupling of the (L)-histidine methyl ester to 1 leads to a derivative we call A21 (2) (Figure 2). This new derivative maintains the same effectiveness as 1 as an antifungal agent and a superior profile of toxicity. For example, the lethal dose 50 (LD50) of 1 in Balb-C mice, by intravenous administration for 48 hours is 4.13 mg/Kg, whereas for 2 it is 49.82 mg/kg, showing an increased margin of safety.


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OH H3C HO

OH

O O CH3

OH

OH

OH

OH

OH H N

O

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O OCH3

O

H3C

N H O

O

HO

2

CH3 N OH

NH2

Figure 2. A21(2), an amphotericin B amide derivative

This new derivative 2 is a new antibiotic that has been tested extensively in microbiological and pre-clinical trials, as well as in electro physiological and spectroscopic experiments that have permitted to assess its antimycotic effectiveness similar to 1, but with a much increased margin of safety, due to a different aggregation on aqueous solutions with respect to the parent molecule.18 This difference affects the incorporation of the polyene into the cellular membrane19 and therefore affects the expression of the polyene channels which are very dependent on membrane structure.20 Certain pre-clinical tests, as long term use, or pharmacokinetic assesment, as well as going into clinical trials, required the synthesis of multigram lots. This paper describes the synthesis of 2, an isolation protocol, and its full characterization by NMR studies.

RESULTS AND DISCUSSION

The first synthesis of 2 was carried out following the protocol reported by Jarsebski11a using diphenylphosphoramide azide as the coupling agent, in basic media followed by the addition of


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(L-)-histidine methyl ester dihydrochloride, which in turn was prepared as described by Kavalainen for (D)-histidine.21 (Scheme 1). These reaction conditions afforded 2 in 94% yield.

a) Ph2PON3, Et3N, N,N-DMAc, (L)-histidine methyl ester (94%). (b) PyBOP, Et3N, DMSO, (L)-histidine methyl ester (97%).

Scheme 1. Methods of synthesis of A21 (2)

Later on, an improved synthesis of 2 was accomplished following the procedure reported by Preobrazhenskaya using benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) as the coupling agent.12a The use of PyBOP as a coupling agent has been widely studied22 and in our case led to the formation of 2 in higher yield (90-97%) and a more pure form. The isolation of 2 was performed by precipitation from the dimethyl sulfoxide (DMSO) solution by the addition of dry acetone, centrifugation and vacuum drying. When trying to replicate on a 1.0 g scale the methodology developed in microscale, we confronted different problems. We found that the reaction was never complete, and found that one of the main causes was the moisture contained in commercial amphotericin B (4.5% by Karl-Fisher). This variable was never considered in the microscale synthesis, as a sample of at least 500 mg was needed for this analysis. It was necessary, then, to develop a drying procedure that would comprise a temperature below 18-20 °C, which was accomplished with a Kugelrohr apparatus and a freezedrying pump, with a vacuum of 2.5 X 10-3 mmHg.


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With dry amphotericin, we started to scale the reaction conditions developed for microscale described in the General Procedure for the PyBOP mediated synthesis of 2. After optimizing the drying conditions, we did several experiments obtaining up to 80-85% of 2. However, when we tried to omit the extraction with diethyl ether, by carrying out just a precipitation with acetone, the product obtained was very toxic. An HPLC-mass analysis showed an impurity, which was characterized as 1,1´,1´´-phosphoryltripyrrolidine, formed from the coupling agent PyBOB. This impurity was removed by extensive washing of the reaction mixture with methyl t-butyl ether (MTBE) before the isolation of 2. In scaling the synthesis to 10.0 g of 1, we had a slightly exothermic reaction, which was controlled using a water bath. Finally, the scaling to 100.0 g was carried out without any inconvenience, taking into account all the above details. This led to the production of 2 in a 97% yield. According to the European Pharmacopeia 8.0, the use of AmB (1) for therapeutic purposes may contain up to four detectable impurities, mainly Nystatine and Amphotericin A; although it may also contain amphotericin X1 (13-O-methylated) and amphotericin X2 (13-O-ethylated). Taking into account that 1 is obtained from a fermentation process with less than 90% purity and the above mentioned impurities, the elaboration of pharmaceutical products from 1 must not exceed 15% of impurities. As a reference standard for 2 is not commercially available, the HPLC analysis only showed a peak integration area that gave an estimation of purity. In the HPLC chromatograms it was found a peak with an integration area percent of 84% for 2 and a peak with an integration area percent of 89% for Amphotericin B USP standard (Figures S1-3, supporting information). We are currently making efforts to obtain a sample of 2 with high purity for its use as a standard for HPLC.


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The structure of 2 was fully supported by a complete 700 MHz NMR study. Details of this characterization is provided in the supporting information. CONCLUSION We have developed a new procedure to couple an amino acid such as (L)-histidine methyl ester dihydrochloride to 1, which was scaled up to 100 grams with good yields and a simple procedure for its isolation. This allowed the development of a synthetic procedure for the synthesis of 2 at a 100 g scale with a yield of 97%, which represents a significant improvement of the original procedure in terms of percentage yield and purity. We have also developed an analytical protocol via HPLC to follow the course of the reaction assuring complete conversion of 1 to the new derivative 2, with the required purity for all biological tests (see supporting information). EXPERIMENTAL SECTION General Procedure for the diphenylphosphoril azide-mediated synthesis of 2. In a threenecked round bottom flask 0.250 g (0.272 mmole) of 1 was dissolved in 5.0 mL of dimethylacetamide (DMAC) under a nitrogen atmosphere. To this solution, 0.38 mL (2.72 mmole) of trimethylamine, 0.652 g (2.72 mmole) of (L)-histidine methyl ester dihydrochloride and 0.58 mL (2.72 mmole) of diphenylphosphoril azide were added at room temperature. The reaction mixture was stirred at room temperature and on the absence of light and monitored until the reaction was over (72 hours). The product was precipitated by addition of 50.0 mL of anhydrous ether and stored overnight at 0 °C. The ether was decanted and the product was dissolved in a minimum amount of n-butanol and washed with distilled water (2 X 100 mL). The n-butanol-water azeotropic mixture was distilled under reduced pressure (100 mm Hg, 50 °C) and the product was again precipitated by addition of 50.0 mL of ether and stored at 0 °C for 12


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hours. The diethyl ether was decanted once again and the product was now washed with ether (50 mL) and hexane (50 mL) and dried under vacuum overnight to afford 2 as a yellow solid. The product was obtained in 84.9% yield and isolated as a yellow solid with mp 142-146 ºC (dec). General Procedure for the PyBOP mediated synthesis of 2. In a 25 mL round bottom flask covered with aluminum foil, Et3N was added drop wise to a solution of 1 (0.195 mmol) and (L)histidine methyl ester hydrochloride (0.409 mmol, 2.1 eq.) in DMSO (3.0 mL) until pH = 8. The resulting mixture was stirred for 15 minutes and then, PyBOP (0.292 mmol, 1.5 eq.) was added under a nitrogen atmosphere, the flask was sealed and stirred for 72 h at room temperature until the reaction was complete (TLC system: methanol–chloroform–water 20:10:1 v/v). The reaction mixture was extracted with anhydrous diethyl ether (5 x 5 mL) and the product was precipitated with anhydrous acetone (5 x 30 mL). The suspension obtained was centrifuged at 2381 x g for 10 minutes, the solvent was decanted and the product dried at reduced pressure to obtain a yellowish powder corresponding to the AmB derivative 2. The product was obtained in yield 84.9% and isolated as a yellow solid with mp 140-145 ºC (dec). Multigram synthesis of 2. In a 3 L, three neck round bottom flask covered with aluminum foil with a mechanical stirrer, thermometer, nitrogen inlet and outlet, placed in a water bath, was loaded in the absence of light, with high vacuum dried 1, 100 g (108.22 mmoles), (L)-histidine methyl ester dihydrochloride, 52.40g (216.45 mmoles), PyBOP 112.74 g (216.45 mmol), DMSO 1.0 L, and 67.81 mL (487.01 mmoles) of triethylamine were slowly added while maintaining the temperature between 23 oC and 25 oC. The reaction mixture was stirred at 250 rpm for 24 hours, and the end of the reaction was checked by HPLC. The reaction mixture was transferred to a 3 L separatory funnel and extracted with MTBE (6 X 1 L). Five liters of acetone were added and the


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suspension was centrifuged (4 °C, 5 min at 3400 x g), and the pellet was res-suspended in 1.0 L of acetone (protected from light) and centrifuged at the same conditions. This operation was repeated two more times, the pellet obtained was re-suspended in 1 L of MTBE and centrifuged again. The pellet obtained was vacuum dried at 20 oC until constant weight obtaining 114.37 g (97% yield). IR vmax 3274.23 cm–1 (s, OH, NH2), 1652.38 cm–1 (s, C=O amide). 1

H NMR (700 MHz, DMSOd-6) δ 8.55 (d, J = 7.1 Hz, 1H, H-51), 8.33 (br, 1H), 7.21 (s, 1H, H-

52), 6.48 – 6.07 (m, 12H, olefinic, H-21 –H- 32), 5.95 (dd, J = 15.1, 8.8 Hz, 1H, H-20), 5.82 (s, 1H), 5.45 (dd, J = 14.9, 9.9 Hz, 1H, H-33), 5.37 (s, 1H), 5.22 (s, 1H, H-37), 4.8 - 4.72 (m, 2H), 4.45 (m, 2H, H-48, H-13), 4.35 (br, 1H, H-41), 4.31 (br, 1H, H-19), 4.24 (br, 1H), 4.18 (t, J = 9.6 Hz, 1H), 4.09 – 3.99 (m, 2H, H-3), 3.86 (s, 1H), 3.65 (s, 3H, H-54), 3.54 (s, 1H, H-5), 3.48 (s, 1H), 3.27 (m, 2H, H-45, H-42), 3.15 – 3.09 (m, 5H, H-49, H-35), 2.96 (d, J = 8.5 Hz, 1H, H-44), 2.29 (m, 1H, H-34), 2.18 (d, J = 5.9, 5.9 Hz, 1H, H-2), 2.02 (m, 1H), 1.90 (m, 1H), 1.73 (m, 1H, H-36), 1.68 (m, 1H), 1.62 – 1.51 (m, 4H, H-4), 1.44 – 1.26 (m, 8H, H-4), 1.19 (d, J = 5.3 Hz, 3H, H-46), 1.15 - 1.11 (m, 6H, H-38), 1.04 (d, J = 6.2 Hz, 3H, H-40), 0.92 (d, J = 7.0 Hz, 3H). 13

C NMR (176 MHz, DMSOd-6) ) δ 172.19 (C-47), 171.21 (C-53), 170.53 (C-1), 136.80 (C-33,

C-20), 133.94, 133.9 (C-52), 133.69, 133.50, 133.20, 132.44, 132.38, 132.17, 131.86, 131.76, 131.18, 128.58, 117.15 (C-51), 97.09 (C-13), 96.04 (C-41), 77.11, 75.21, 73.72 (C-19), 73.60, 72.55 (C-42), 69.14 (C-5), 68.91 (C-37), 68.70 (C-45), 67.67, 67.10, 66.20 (C-3), 65.11, 65.04, 56.44, 55.50 (C-44), 52.21 (C-48), 52.07 (C-54), 48.72, 46.22, 44.75, 44.69 (C-4), 42.36 (C-34), 42.06 (C-2), 42.02 (C-36), 40.02, 36.33, 35.05, 28.97, 26.83(C-49), 18.48 (C-40), 17.72 (C-46), 16.98 (C-38), 12.06 (C-39). HRMS (FAB+): m/z [M + H]+ for C54H82N4O18 calcd: 1075.5702, found: 1075.5719.


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ASSOCIATED CONTENT Supporting Information. 1

H NMR, 13C NMR spectra of AmB (1) and A21 (2). HPLC of A21 (2).

AUTHOR INFORMATION Corresponding Authors * E-mail: [email protected]. Phone: (+52) 777 329 7997. * E-mail: [email protected]. Phone: (+52) 55 5623 0795 Author Contributions The manuscript was written through contributions of all authors. / All authors have given approval to the final version of the manuscript. Funding Sources Iván Ortega-Blake received funding from the National Autonomus University of México (UNAM-DGAPA-PAPIIT) Grant IG100416. Mario Fernández-Zertuche received funding from the National Science and Technology Council (CONACyT) of México Grant 241088. Notes The authors declare no competing financial interests. REFERENCES (1) (a) Hartsel, S. C., Bolard, J. Trends Pharmacol. Sci. 1996, 12, 445-449. (b) Gallis, H. A., Drew, R. H., Pickard, W. W. Rev. Infect. Dis.1990, 12, 308-329. (c) Lemke, A., Kiderlen, A. F., Kayser, O. Appl. Microbiol. Biotechnol. 2005, 68, 151-162. (d) Brajtburg, J., Bolard, J. Clin. Microbiol. Rev. 1996, 9, 512-531. (e) Cereghetti, D.; Carreira, E.M. Synthesis 2006, 6, 914-942.


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