Sagopilone
| |
| Names | |
|---|---|
| IUPAC name
(1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,12,16-tetramethyl-3-(2-methyl-1,3-benzothiazol-5-yl)-10-prop-2-enyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
| |
| Identifiers | |
3D model (JSmol)
|
|
| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| DrugBank | |
| ECHA InfoCard | 100.207.513 |
| EC Number |
|
| KEGG | |
PubChem CID
|
|
| UNII | |
CompTox Dashboard (EPA)
|
|
| |
| |
| Properties | |
| C30H41NO6S | |
| Molar mass | 543.72 g·mol−1 |
| Hazards | |
| GHS labelling:[1] | |
 
| |
| Danger | |
| H300, H341, H361 | |
| P203, P264, P270, P280, P301+P316, P318, P321, P330, P405, P501 | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
| |
Sagopilone is a fully synthetic macrolide of the epothilone family with the molecular formula C30H41NO6S. The mechanism of action is similar to taxanes, as they bind to the microtubule and prohibit cell devision. These toxic properties and its possibility to cross the blood-brain barrier makes it a promising cancer medication.
Substance class
Sagopilone, also known as ZK-EPO belongs to the epothilones which are formed out of polyketides.
Structure
Sagopilone is a 16-bond macrolide structure, a macrocycle with inner ester structure. With its C30H41NO6S formula and a molecular weight of only 543.7 g/mol sagopilone belongs to the low molecular weight epothilones
Sagopilone has similarities in structure and mechanism of actions with epothilone, especially epothilone B. The mechanism of action is similar to the taxanes. It binds to the microtubule of the cell and therefore prevents cell division. Which makes it acutely toxic.
Sagopilone contains 2 hydrogen bond donor and 8 acceptor, 3 rotatable bonds and 7 stereocenters.
Synthesis
Sagopilone is a completely synthetic product. The molecule can be divided into three blocks (A, B, and C).
First, each of the blocks is to be synthesised parallelly. Then, the blocks are combined, starting with the fusion of B and C and then adding A.
The blocks include carbon atoms C1 to C6, C7 to C12, and C13 to C15 of the final structure correspondingly. Blocks A and B derive from readily available chiral structures, (-) Pantolactone and the Roche Ester, whereas block C originates from the achiral benzoic acid.
Block BC is built by the Wittig reaction between ketone B10 and the ylene generated from salt C12. Aldol reactions, specificaly the Swern oxidation makes up the last step in building Block BC, the aldehyde BC3.
The final sequence ABC requires macrocyclization of the compartements A13 and BC3 which take place in the form of yamaguchi macrolactonization.
Synthesis of the block A
Block A is synthesised in a chiral pool synthesis with stable intermediate products. Therefore, large scale production is possible.
The process starts with cheap (-) Pantolactone(1), which already includes C2 to C5 carbon atoms of the final structure as well as the dimethyl at C4. The stereogenic centre is located at C3. After the hydroxyl group at C3 is protected as a tetrahydropyranyl (TPH) ether (2), diisobutylaluminum hydride (DIBAH) reduces the lactone to a lactol (3).
A Wittig reaction with methyl phosphorus-ylide introduces the yet missing C1 to the molecule giving (4).
Following, the alcohol at C5 is protected as a benzyl ether. Then, the olefin (5) undergoes a Brown-hydroboration followed by an oxidation (6 a-c). As a consequence, the double bond between C1 and C2 is replaced by a single bond and a hydroxyl group is added at C1.
Three different isomers emerge from this reaction. (a) and (b) differ in the substituent at C3 while both carry a hydroxyl group at C1. (a) keeps the THP ether, (b) presents with an unprotected hydroxyl group at C3.
Unlike (a) and (b), (c) presents the hydroxyl group at C2 therefore being a secondary alcohol. The (a) and (b) structures are separated by chromatography and react with 2,2 dimethoxypropane to form acetonide (7), a stable key intermediate of the synthesis.
In preparation for a Swern-oxidation of the alcohol at C5, the benzyl ether is cleaved (8).
An aldehyde is the product of the Swern-oxidation (9). Reaction with 1-butenyl-4-magnesium bromide adds a homoallyl rest to the molecule (10).
At last, the molecule undergoes oxidation to form the final structure (11).[2]
Synthesis of the block B
The chiral pool synthesis of the block starts with the Roche Ester (1).
First, the hydroxy group at C7 is protected as a tetrahydropyranyl ether (2).
The following reduction of the ester moiety results in a primary alcohol (3) which is protected as a tosylate (4).
In a separate reaction, the primary alcohol (5) is derivatized to an alkyl bromide (6), which fuses with the tosylate to (7). The double bond undergoes bishydroxylation and thereafter oxidative degradation which provides the final methyl ketone (8).[3]
Synthesis of the block C
Starting material for the block C is the achiral benzoic acid (1). In a reaction with sodium sulfide, acetic anhydride and acetic acid benzothiazole (2) is built.
Following, LAH reduces the carboxylic acid of the benzothiazole to a primary alcohol (3) which is directly oxidised to an aldehyde (4).
In an Evans Aldol reaction, 3-acetyl-(4S,5R)-4-methyl-5-phenyl-2-oxazolidinone is added which leads to the formation of (5) with a stereogenic centre at C15. The secondary alcohol is protected as a TBDMS ether (6) in a silylation.
The following transesterification gives (7) and recovers the chiral auxiliary following, DIBAH reduces the ether moiety to a primary alcohol (8), which transforms into an iodide (9). The final product of the block C, a phosphonium salt, is achieved by crystallisation.
After synthetizing each sequence, A, B and C, the sequences must be connected.
Building Block BC
Block BC is synthetized by the Wittig reaction between ketone B10 and the ylene generated from salt C12. The reaction was performed without isolation of the hygroscopic salt.
Triphenylphosphine was added to a THF solution of iodide C11 and refluxed for 24 hours. The solution was cooled to 0°C, building block B10 and a solution of NaHMDS in THF were added. Then the solution was stirred for 20 hours at 20°C and then worked up under aqueous conditions to give a quantitative yield of (E/Z)-BC1. BC1 is afforded as a nearly 1:1 mixture of E/Z isomers.
The E/Z isomers can be separated by chromatography to yield stereochemically pure (Z) BC2 and (E ) BC2 after the tetrahydropropanyl ether was cleaved with (-)- camphorsulfonic acid in 2-PrOH at 35°C. The undesired isomer (E )- BC2 was recycled by photochemical isomerization of the double bond (by irradiation with UV light (above 280nm)) to get a 3:2 to 1:1 mixture of (E )- and (Z)- BC2 isomers in a total yield of over90%.
After two iterative irradiations and separations the overall yields from C11 to (Z)- BC2 was 70-75%. The alcohol (Z)- BC2 was then oxidized to BC3, the aldehyde, under standard conditions and isolated as a solution in n- hexane for the following aldol reaction (Swern oxidation).[4][5]
To get the final Sequence ABC, the Sagopilone, BC3 (Aldehyde) was reacted with block A13.
Building Final Sequence ABC: Sagopilone
The final sequence is built up by A13 and BC3 in an aldol reaction to yield ABC1 in good diastereoselectivity (minor amounts of its diastereoisomer had to be removed by chromatography). To an LDA solution in THF, A13 was added at -60°C. Then, a solution of ZnCl2 in THF at -80°C was added. Adding ZnCl2 was crucial in terms of reproducibility and robustness for up-scaling of this reaction. Zinc chloride improved the diastereoselectivity (about 10:1).
BC3, the aldehyde, was added at -80°C and the solution stirred at -80°C. The aldol product ABC1 was given in 75-78% yield after aqueous workup and chromatographic purification.
Copper (II) chloride was added to a solution of ABC1 in acetonitrile followed by a catalytic amount of water. The solution was stirred at 20°C resulting in a quantitative conversion. The reaction was stopped by addition of triethylamine, worked up, and the triol ABC2 isolated as a solution in dichloromethane which was used directly in the following silyliation with TBDMSOTf and 2,6-lutidine. The product was yield in 90-95% (over two steps) in aqueous workup and isolation in dichloromethane solution.
ABC1 (the ketal) was cleaved, the resulting triol ABC2 globally TBDMS-protected and the primary silyl ether in ABC3 was selectively removed under mild acidic conditions to give ABC4 which was oxidized in two steps to the carboxylic acid ABC6. The selective cleavage of the primary TBDMS groups was performed with camphorsulfonic acid in 2:1 mixture of CH2-Cl2-MeOH.
The alcohol ABC4 was obtained in 76-82% yield after aqueous workup.
ABC6 was carried out in Swern oxidation, and the product was isolated in THF solution. To get ABC7 in over 95%, the solution was directly treated with TBAF at 20°C and isolated as THF solution again.
Then the allylic alcohol was deprotected and the crude hydroxy acid subjected to Yamaguchi cyclization conditions to give lactone ABC8.
The hydroxic acid ABC7 reacted in a first step with 2,4,6- trichlorobenzoyl chloride (Hüning base) and DMAP to form the mixed anhydride. This solution was added to a solution of DMAP in dichloromethane at 20°C over 14 hours.
After aqueous workup and chromatography, the lactone ABC8 was obtained in 75-85%. At 20°C with HF-pyridine the deprotection to the diol ABC9 was done. Alkaline conditions resulted in a partial opening of the lactone ring. ABC9 was isolated in 83% yield in dichloromethane solution after workup.
The remaining protecting groups were removed to yield the modified epothilone D analogue ABC9. Epoxidation of the double bond with dimethyldioxirane (DMDO) afforded the alpha-epoxide ABC10 with high stereoselectivity along with minor amounts of the biologically less active beta-epoxide (7-8:1). The final processing was performed by crystallization from a toluene-hexane mixture to give the drug substance ABC10 in 94%yield.
The longest linear sequence (C1-> BC3 -> ABC10) involved 22 steps.[6][7]
Biological effects and usage
Epothilones are a novel class of natural microtubules-stabilizing products. They show potential activity in an expanded spectrum of tumor indications.
Microtubules are polymeric structures. They are composed of alpha- and beta-tubulin heterodimers. Sagopilone induces tubulin polymerization and therefore shows antitumor activity.
In the cell, sagopilone localizes predominantly to the cytoskeletal compartment. Sagopilone treated cells show mitotic abnormalities which lead to induction of cell cycle arrest at metaphase (in HCT116 cells). Induction of the apoptosis follows together with mitochondrial transmembrane potential dissipation (activation of caspase-3 and - 9, mitochondrial cytochrome c release).
Sagopilone was tested in phase II clinical trials and has been shown to be clinically active in platinum- resistant and -sensitive ovarian cancer, NSCLC, prostate cancer, glioblastoma and melanoma tumor cells.[8][9]
References
- ^ "Sagopilone". pubchem.ncbi.nlm.nih.gov.
- ^ Klar, Ulrich; Röhr, Bodo; Kuczynski, Frank; Schwede, Wolfgang; Berger, Markus; Skuballa, Werner; Buchmann, Bernd (2005). "Efficient Chiral Pool Synthesis of the C1-C6 Fragment of Epothilones". Synthesis. 2005 (2): 301–305. doi:10.1055/s-2004-834936.
- ^ Klar, Ulrich; Buchmann, Bernd; Schwede, Wolfgang; Skuballa, Werner; Hoffmann, Jens; Lichtner, Rosemarie B. (4 December 2006). "Total Synthesis and Antitumor Activity of ZK-EPO: The First Fully Synthetic Epothilone in Clinical Development". Angewandte Chemie International Edition. 45 (47): 7942–7948. doi:10.1002/anie.200602785. PMID 17006870.
- ^ Examples for two Z- selective methodologies Prantz, Kathrin; Mulzer, Johann (11 January 2010). "Synthesis of ( Z )-Trisubstituted Olefins by Decarboxylative Grob-Type Fragmentations: Epothilone D, Discodermolide, and Peloruside A". Chemistry – A European Journal. 16 (2): 485–506. doi:10.1002/chem.200901567. PMID 19943284.
- ^ Nicolaou, K. C.; Hepworth, David; King, N. Paul; Finlay, M. Raymond V.; Scarpelli, Rita; Pereira, M. Manuela A.; Bollbuck, Birgit; Bigot, Antony; Werschkun, Barbara; Winssinger, Nicolas (4 August 2000). "Total Synthesis of 16-Desmethylepothilone B, Epothilone B10, Epothilone F, and Related Side Chain Modified Epothilone B Analogues". Chemistry - A European Journal. 6 (15): 2783–2800. doi:10.1002/1521-3765(20000804)6:15<2783::AID-CHEM2783>3.0.CO;2-B. PMID 10985727.
- ^ Altmann, Karl-Heinz; Bold, Guido; Caravatti, Giorgio; Flörsheimer, Andreas; Guagnano, Vito; Wartmann, Markus (December 2000). "Synthesis and biological evaluation of highly potent analogues of epothilones B and D". Bioorganic & Medicinal Chemistry Letters. 10 (24): 2765–2768. doi:10.1016/S0960-894X(00)00555-2. PMID 11133086.
- ^ Herrmann, Wolfgang A.; Fischer, Richard W; Marz, Dieter W. (December 1991). "Methyltrioxorhenium as Catalyst for Olefin Oxidation". Angewandte Chemie International Edition in English. 30 (12): 1638–1641. doi:10.1002/anie.199116381.
- ^ Clin Oncol 2007, 25, p. 3415-20
- ^ Marupudi, Neena I; Han, James E; Li, Khan W; Renard, Violette M; Tyler, Betty M; Brem, Henry (September 2007). "Paclitaxel: a review of adverse toxicities and novel delivery strategies". Expert Opinion on Drug Safety. 6 (5): 609–621. doi:10.1517/14740338.6.5.609. PMID 17877447.