Novel unit B cryptophycin analogues as payloads for targeted therapy

Article abstract of DOI:10.3762/bjoc.14.109

Cryptophycins are naturally occurring cytotoxins with great potential for chemotherapy. Since targeted therapy provides new perspectives for treatment of cancer, new potent analogues of cytotoxic agents containing functional groups for conjugation to homing devices are required. We describe the design, synthesis and biological evaluation of three new unit B cryptophycin analogues. The O-methyl group of the unit B D-tyrosine analogue was replaced by an O-(allyloxyethyl) moiety, an O-(hydroxyethyl) group, or an O-(((azidoethoxy)ethoxy)ethoyxethyl) substituent. While the former two maintain cytotoxicity in the subnanomolar range, the attachment of the triethylene glycol spacer with a terminal azide results in a complete loss of activity. Docking studies of the novel cryptophycin analogues to β-tubulin provided a rationale for the observed cytotoxicities.

Full text of DOI:10.3762/bjoc.14.109

Novel unit B cryptophycin analogues as payloads for
targeted therapy
Eduard Figueras, Adina Borbély, Mohamed Ismail, Marcel Frese and Norbert Sewald*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1281–1286.
Department of Chemistry, Organic and Bioorganic Chemistry,
Bielefeld University, Universitätsstraße 25, 33615 Bielefeld, Germany
doi:10.3762/bjoc.14.109
Received: 16 February 2018
Accepted: 02 May 2018
Published: 01 June 2018
Email:
Norbert Sewald* - Norbert.sewald@uni-bielefeld.de
* Corresponding author
This article is part of the Thematic Series "Peptide–drug conjugates".
Associate Editor: A. Kirschning
Keywords:
cryptophycin; cytotoxic agents; novel payloads; tubulin inhibitors;
tumour targeting
© 2018 Figueras et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Cryptophycins are naturally occurring cytotoxins with great potential for chemotherapy. Since targeted therapy provides new
perspectives for treatment of cancer, new potent analogues of cytotoxic agents containing functional groups for conjugation to
homing devices are required. We describe the design, synthesis and biological evaluation of three new unit B cryptophycin ana-
logues. The O-methyl group of the unit B D-tyrosine analogue was replaced by an O-(allyloxyethyl) moiety, an O-(hydroxyethyl)
group, or an O-(((azidoethoxy)ethoxy)ethoyxethyl) substituent. While the former two maintain cytotoxicity in the subnanomolar
range, the attachment of the triethylene glycol spacer with a terminal azide results in a complete loss of activity. Docking studies of
the novel cryptophycin analogues to β-tubulin provided a rationale for the observed cytotoxicities.
Introduction
Cryptophycins are natural occurring cyclic depsipeptides that neurotoxic side effects forced the termination of the clinical
were first isolated from cyanobacteria Nostoc sp. ATCC 53789 trials [21-23]. In order to overcome the side effects of crypto-
in 1990 [1]. Cryptophycins target tubulin, in particular the phycin-52 and to better understand the fundamental structure
peptide site of the vinca domain. They block microtubule for- for biological activity, numerous structure–activity relationship
mation, inhibiting their assembly and, hence, are antimitotic studies have been carried out [24-35]. However, like crypto-
agents [2,3]. Their high cytotoxicity prompted manifold studies phycin-52, the new analogues were not selective against cancer
that were initially focussed on the total synthesis and cells making them not better than its parent.
structure–activity relationships [4-20]. This work resulted in the
identification of cryptophycin-52, a highly biologically active In recent years the targeted delivery of cytotoxic agents has
analogue of cryptophycin-1 (Figure 1).
emerged as a highly promising method to tackle selectivity
issues [36-40]. Cryptophycin-52 and many analogues lack an
Eli Lilly took cryptophycin-52 into clinical trials. Although addressable group to conjugate the toxin to a homing device.
almost half of the patients obtained a benefit from the treatment, For this reason, new analogues containing functional groups
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Beilstein J. Org. Chem. 2018, 14, 1281–1286.
less cleavable linkers that are sensitive to the distinct physi-
ology of the tumour with enhanced level and activity of specif-
ic enzymes. The connection between the payload and the linker
is of crucial importance since its stability can dramatically
change the release and thus, the activity of the compound. For
this reason, the included functional groups were designed with
the consideration to provide appropriate stability and activity to
the future conjugate.
Results and Discussion
Design and synthesis
Figure 1: Cryptophycin-1 (1) and -52 (2).
Previous docking studies have postulated that the methyl group
that would allow the conjugation of a homing device were de- of unit B is not involved in the cryptophycin–tubulin interac-
veloped [41-46]. Some of these functionalized analogues have tion [52]. Moreover, its absence did not produce a dramatic loss
been recently used for the preparation of antibody–drug conju- of activity [24].
gates (ADCs) and peptide–drug conjugates (PDCs) [46-51].
Nevertheless, there is still a strong need of novel cryptophycin Based on this, we designed cryptophycin analogues modified in
analogues with maintained activity containing a suitable func- the unit B. Instead of the O-methyl group that is present in the
tional group that would allow the conjugation to the homing natural cryptophycin, we attached a hydroxyethyl group or a
device. Cryptophycin-1 contains a methoxy group in the aro- triethylene glycol chain terminated with an alcohol or azide, re-
matic ring of the unit B, which is a chlorinated derivative of spectively. These functional groups would allow the conjuga-
D-tyrosine. Different chains for unit B have been investigated, tion of the novel cryptophycin analogues across an appropriate
albeit the elongation of the methoxy group is still unknown. linker to an antibody or peptide. Either a virtually uncleavable
Therefore, in the current study, we embarked on the synthesis of triazole (introduced by CuAAC) or scissile ester, carbonate, or
novel cryptophycin analogues containing different substituents carbamate moieties were taken into account.
at the phenolic hydroxy group of the unit B. We intended to in-
vestigate whether the high biological activity of the parent com- The synthesis of the modified unit B (Scheme 1) started with
pound is retained and thus, construction of ADCs and PDCs the preparation of the two different spacers that were later
would be feasible. This preparation could be done using trace- connected to the phenol. Starting from triethylene glycol (3) or
Scheme 1: Synthesis of modified unit B (13 and 14). Reagents and conditions: (a) 1) TsCl, DMAP, Et3N, CH2Cl2, rt, 4 h; 2) NaN3, DMF, 70 °C,
overnight; (b) TsCl, Et3N, CH2Cl2, rt, overnight; (c) NaI, acetone, reflux, overnight; (d) TsCl, Et3N, CH2Cl2, rt, overnight; (e) NaI, acetone, reflux,
overnight; (f) 6 or 9, K2CO3, DMF, 50 °C, overnight; (g) LiOH, H2O/MeOH/THF 1:1:1, rt, 2 h.
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2-allyloxyethanol (7) tosylations and nucleophilic displace- [45]. Then, Fmoc was cleaved from the N-terminus of unit
ments by azide or iodide substitution provided 6 and 9 in good C–D–A (17) using piperidine and the resulting crude amine was
yields. O-Alkylation of Boc-protected 3-chlorinated D-tyrosine coupled to the corresponding modified unit B (13 or 14),
10 with 6 or 9 gave 11 and 12, again in satisfactory yields affording the according linear cryptophycins 18 and 19 in
(81–85%). Saponification of the ester moiety in 11 and 12 that acceptable yields (51–59%). Compounds 18 and 19 were
was formed concomitantly with the O-alkylation in the previous treated with trifluoroacetic acid for simultaneous Boc and t-Bu
reaction provided Boc-protected modified units B 13 and 14 in removal, which also cleaved the dioxolane ring. Subsequently,
76 and 90% yield, respectively.
macrolactamization was performed under pseudo-high-dilution
conditions to afford 20 and 21 as described previously [16].
The synthesis of units C–D and A succeeded as previously de- Then the diol was transformed into the epoxide following a
scribed in the literature; unit A (15) and C–D (16) were three-step one-pot reaction as extensively used in the synthesis
connected by Yamaguchi esterification to give 17 (Scheme 2) of cryptophycin analogues [46]. Cryptophycin analogues 22 and
Scheme 2: Synthesis of cryptophycin analogues 22, 23 and 24. Reagents and conditions: (a) 4-DMAP, 2,4,6-trichlorobenzoyl chloride, Et3N, THF,
0 °C, 3 h; (b) 1) piperidine, DMF, rt, 2 h; 2) 13 or 14, HOAt, EDC·HCl, Et3N, CH2Cl2, 0 °C → rt, overnight; (c) 1) TFA/CH2Cl2/H2O, rt, 2 h; 2) HATU,
HOAt, DIPEA, DMF, rt, slow addition + 2 h; (d) 1) (CH3O)3CH, PPTS, CH2Cl2, rt, 2 h; 2) AcBr, CH2Cl2, rt, 4 h; 3) K2CO3, DME/ethylene glycol
(2:1 v/v), rt, 5 min; (e) Pd(PPh3)4, phenylsilane, CH2Cl2, rt, 7 h.
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Beilstein J. Org. Chem. 2018, 14, 1281–1286.
23 were obtained in good purity after column chromatography. [52], the methoxy group of subunit B forms a hydrogen bond
The allyl ether in 23 was cleaved using Pd(PPh3)4 as Pd(0) with Lys176 (Figure 2). Another binding mode of 2 with
source and phenylsilane as scavenger to obtain the crypto- high binding affinity and hydrogen bond formation did not
phycin analogue 24 in good purity.
involve any interaction of subunit B, yet it was oriented
towards the GDP binding site that might influence GTP hydro-
lysis.
Biological evaluation
The biological activity of the modified unit B analogues was de-
termined in a cell viability assay using the human cervix carci-
noma cell line KB-3-1 (Table 1). The cryptophycin analogue 22
showed a dramatic loss of activity compared to cryptophycin-52
(2), while analogues 23 and 24 showed a reduced cytotoxicity
although their IC50 values are still in the low nanomolar range.
The observed dramatic loss of activity of analogue 22 could be
due to its poor internalization or the modification could alter the
interaction with tubulin. In order to get an extensive knowledge
of the novel analogues, we embarked in docking and modelling
studies, herein reported, and internalization studies are ongoing
in our research group.
Figure 2: Binding mode of 2, showing the interaction to the vinca
domain peptide binding pocket (blue). Hydrogen bonds are shown as
yellow dots with the interacting amino acid residues in magenta.
Table 1: Cytotoxicity of cryptophycin-52 and its unit B analogues.
compd unit B
IC50
KB-3-1
(nM)
Compound 22 with the triethylene glycol-based substituent
prevents correct binding, the binding energy was decreased and
mainly nonspecific interactions outside the binding pocket were
observed (Figure 3). This was not the case for the other deriva-
tives 23 and 24 (Figure 4).
2
CH2Ph(m-Cl,p-OMe)
CH2Ph(m-Cl,p-(OCH2CH2)3N3)
0.015
22
23
24
195000
CH2Ph(m-Cl,p-OCH2CH2OCH2CHCH2) 0.748
CH2Ph(m-Cl,p-OCH2CH2OH) 0.184
Docking and modelling of cryptophycin
derivatives
There is no X-ray analysis of cryptophycin–tubulin complexes
available to provide information on the binding site. Based on
biochemical evidence, binding close to the vinca-alkaloid
binding site of β-tubulin, the so called “peptide-site”, has been
proposed [2,52,53]. We performed a docking study to explain
the different affinities of the newly synthesized derivatives. The
parent compound 2 scored highest with respect to β-tubulin
binding (Table 2). Three hydrogen bonds were detected to key
residues in the peptide binding pocket of the vinca domain
(Lys176, Val177 and Tyr210). Other than previously reported
Figure 3: Docking of 22 to the vinca domain of β-tubulin. Surface and
backbone of β-tubulin are shown in blue, GDP in yellow. No hydrogen
bond formation was detected. The orientation of the azidoethoxy-
ethoxyethyl substituent prevents the inhibitor from the correct interac-
tion with the protein. The epoxide and benzyl group of subunit A are
pointing away from the binding pocket.
Table 2: Binding energies for the different cryptophycin analogues.
compd
binding
energy
(kJ/mol)
max. binding min. binding
energy
energy
(kJ/mol)
(kJ/mol)
2
36.17
22.61
32.20
32.70
36.17
22.61
32.20
32.70
17.21
5.44
22
23
24
Besides hydrogen bond formation and binding affinity of inhibi-
tors 2, 23 and 24, π-interactions and hydrophobic contacts with
the binding pocket of the vinca domain were detected
10.38
11.72
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ORCID® iDs
Eduard Figueras - https://orcid.org/0000-0002-1853-9974
Adina Borbély - https://orcid.org/0000-0002-5506-6555
Norbert Sewald - https://orcid.org/0000-0002-0309-2655
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