Synthesis and cytotoxicity of leinamycin antibiotic analogues

Article abstract of DOI:10.1021/jm060471h

A simple synthesis of 1,2-dithiolan-3-ones from α,β-unsaturated thiophenyl esters is reported. Introduction of the biologically active 1,2-dithiolan-3-one-1-oxide moiety of leinamycin into aldehydo-D-arabinose 11, the uridine derivative 16, and the deoxyt

Full text of DOI:10.1021/jm060471h

5626
J. Med. Chem. 2006, 49, 5626-5630
Synthesis and Cytotoxicity of Leinamycin Antibiotic Analogues
AÄ kos Szila´gyi,† Ferenc Fenyvesi,‡ Orsolya Majercsik,† Istva´n F. Pelyva´s,† Ildiko´ Ba´cskay,‡ Pa´lma Fehe´r,‡ Judit Va´radi,‡
Miklo´s Vecsernye´s,‡ and Pa´l Herczegh†,*
Department of Pharmaceutical Chemistry and Research Group for Antibiotics of the Hungarian Academy of Sciences,
UniVersity of Debrecen, Egyetem te´r 1, P.O. Box 70 H-4010 Debrecen, Hungary, and Department of Pharmaceutical Technology,
UniVersity of Debrecen, Egyetem te´r 1, P.O. Box 78 H-4010 Debrecen, Hungary
ReceiVed April 20, 2006
A simple synthesis of 1,2-dithiolan-3-ones from R,â-unsaturated thiophenyl esters is reported. Introduction
of the biologically active 1,2-dithiolan-3-one-1-oxide moiety of leinamycin into aldehydo-D-arabinose 11,
the uridine derivative 16, and the deoxythymidine 21 was established. An extended bioactive part of
leinamycin carrying a carbon-carbon triple bond was also synthesized. All of these analogues of leinamycin
showed cytotoxic activity against HeLa3 tumor cells. Interestingly, the lipophilic, silyl group-containing
derivatives proved to be more active than the hydrophilic counterparts.
Introduction
Leinamycin1 is a macrolactam-type antibiotic isolated1,2 from
the fermentation broth of Streptomyces atrooliVaceus in 1989.
Early biological studies have shown that leinamycin is an
antibacterial antibiotic which cleaves single-strand plasmid
DNA,3 and for this effect the presence of a thiol (i.e. 2-mer-
captoethanol, dithiothreitol, glutathione, and propanethiol) is
Figure 1. Structure of leinamycin.
essential. Following structural elucidation,2,4 the synthesis of
the antibiotic was also accomplished.5,6
Scheme 1. DNA Cleavage Mechanism of Leinamycin
To the 18-membered lactam ring of leinamycin is attached a
1,2-dithiolan-3-one-S-oxide ring (Figure 1), which is responsible
for DNA-splitting, and till now, such a ring-system has not been
found as a constituent of a natural product. The biological effect
is manifested in a cytotoxic antitumor activity;3 therefore, this
topic is an intensively studied field.
By chemical transformations, Japanese authors7-9 succeeded
in preparing semisynthetic derivatives of leinamycin possessing
stronger cytotoxic effect than that of the parent antibiotic.
A mechanism for DNA cleavage given10 by the researchers
of the Kyowa Hakko Kogyo (Scheme 1) assumes an episulfo-
nium intermediate formed from the dithiolanone-S-oxide by the
action of the trigger thiol that splits a guanyl radical from the
guanosine portion of the DNA to result in chain cleavage.
Besides this mode of action, on the basis of DNA alkylation,
Gates et al.9,11,12,13 also suggested a thiol-triggered, but oxidative,
DNA splitting, with a major role of oxygen radicals derived
from intermediate C (Scheme 1). The Gates group also observed
the DNA-splitting properties of simple dithiolanone-S-oxide
model compounds. However, the problem appears to be more
Chemistry. As reported in a preliminary paper,16 our primary
goal was to elaborate a new method for the synthesis of the
bioactive heterocyclic ring of leinamycin. According to a general
methodology, the reaction of the starting aldehyde (1) with a
phosphorane affords the R,â-unsaturated E-thiophenyl active
esters (2), whose treatment with SH- anion yields the 3-mer-
captothiolic acid 4. Oxidation of this latter compound leads to
the disulfide-type 1,2-dithiolan-3-one (5), and subsequent oxida-
tion of 5 with dimethyldioxirane then gives rise17 to the S-oxide
6 (Scheme 2).
complicated since Gates et al. have discovered14 an additional
way for the alkylative DNA cleavage of leinamycin that is
independent of thiols, and water serves as the trigger. Although
the DNA splitting of several simple 1,2-dithiolan-3-one-S-oxides
have been demonstrated, only one report15 deals with their
biological activity, and the investigated compounds were found
to be slightly cytostatic or were inactive.
The aim of the present work was to incorporate the 1,2-
dithiolanon-S-oxide molecular fragment of leinamycin into
various simple compounds and to examine the cytotoxic effect1
of the products.
The demonstration of our method (Scheme 3) starts with the
model compound 3-phenylpropionaldehyde (7) and then con-
tinues with 2,3:4,5-di-O-isopropylidene-aldehydo-D-arabinose
(11, Scheme 4).
* Corresponding author. Tel: + 36 52-512-900-22463. Fax: + 36 52-
512-914. E-mail: herczeghp@tigris.klte.hu.
† Department of Pharmaceutical Chemistry and Research Group for
Antibiotics of the Hungarian Academy of Sciences.
‡ Department of Pharmaceutical Technology.
Applying the above general protocol, the reaction of 7 and
11 with phenylthiocarbonylmethylenetriphenylphosphorane,18
10.1021/jm060471h CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/12/2006

Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18 5627
Scheme 2. A New Synthesis of Dithiolanone-S-oxidea
In 1990, Hara et al.3 suggested that combination of the 1,3-
dioxo-1,2-dithiolane DNA cleaving moiety with a DNA rec-
ognition element might provide a novel approach for the design
of new cancer chemotherapeutic agents. On the basis of this,
we thought that incorporation of the “warhead” of leinamycin
into nucleosides might manage delivery to the target point of
action by the formation of a base pair. Therefore, we applied
our procedure to the 5′-aldehyde 16, derived from 2′,3′-di-O-
silyluridine19 (15), and through the intermediates 17, 18a, and
19a, the dithiolane-S-oxides 18b and 19b were obtained
(Scheme 5).
By the oxidation19 of the silyl ether of 2′-deoxythimidine (20)
followed by Wittig reaction, the same sequence shown above
(involving the intermediates 21 and 22) furnished the leinamycin
analogues 23b and 24b (Scheme 6).
An intermediate of the DNA cleavage mechanism of leina-
mycin is the episulfonium salt D (Scheme 1), which is produced
from the 1,2-dithiolan-3-one-S-oxide by incorporation of the
carbon-carbon double bond at γ-position. Recently Lee et al.20
and the Gates group21 have also synthesized simple substances
carrying the above-mentioned structural elements that might be
able to alkylate DNA.
a Reagents: (a) Ph3PCHCOSPh (1.2-1.4 equiv), room temperature, 16-
48 h; (b) Et3N (triethylamine, 2.1 equiv), H2S, 1,4-dioxan, room temperature,
2 h; (c) K3[Fe(CN)6] (1.5 equiv), 1,4-dioxane/water, room temperature, 12-
16 h; (d) dimethyldioxirane (1.0 equiv), acetone, room temperature, 2 h.
Scheme 3. Reactions with 3-Phenylpropionaldehydea
We also decided to investigate the cytotoxic activity of simple
dithiolanone-S-oxides in which a triple bond is present at
γ-position to the heteroring. Consequently, by the Michael
addition of the lithio-cuprate derived from the allyl tetrahydro-
pyranyl ether 25 the derivative 26 was prepared. Subsequent
transformations following our general protocol (Scheme 7) gave
rise to the dithiolanone derivatives 28a and 28b.
a Reagents: (a) Ph3PCHCOSPh (1.3 equiv), toluene, room temperature,
48 h, 80%; (b) Et3N (2.1 equiv), H2S, 1,4-dioxane, room temperature, 2 h;
(c) K3[Fe(CN)6] (1.5 equiv), 1,4-dioxane/water, room temperature, 12 h,
60% (b+c); (d) dimethyldioxirane (1.0 equiv), acetone, room temperature,
2 h, 97%.
Results and Discussion
Investigation of the potential antitumor activity of the
leinamycin analogues was carried out by determining the IC50
values on HeLa-3-tumor cells using daunomycin, useful in tumor
chemotherapy, as the reference material. The IC50 values were
measured in the absence of a thiol and also in the presence of
ethanethiol, assuming that the cytotoxic effect is manifested due
to DNA cleavage and for such an action of leinamycin the
presence of a thiol serving as trigger is necessary.
Scheme 4. Reactions with Arabinosea
Since Padro´n et al.22 reported recently that the presence of
lipophilic silyl groups enhances the cytotoxicity of certain
substances toward human tumor cells, the synthetic intermedi-
ates of the nucleoside derivatives carrying one or more TBDMS
(tert-butyldimethylsilyl) group(s) were also investigated. As the
data presented in Table 1 demonstrate, all of the derivatives
show a cytotoxic effect in micromolar concentrations. However,
only a few of our compounds possessed an activity comparable
to that of daunomycin.
It is also clear that ethanethiol significantly enhanced the
cytotoxic effect in each case, so the assumption that for the
activity of the dithiolanone-S-oxides the presence of a thiol is
necessary is correct. At the same time, it is very interesting that
the cyclic disulfide-type intermediates (9, 13, 18a, 19a, 23a,
24a, and 28a) are also active, although to a less extent than the
corresponding S-oxide analogues (indicated with the sign b),
which are chemically more reactive. In compounds 9, 10, 13,
and 14 the “warhead” was coupled to molecules that are not as
important as considered on the basis of the mechanism of action,
but a slight activity was still observed also in these cases.
The nucleoside derivatives 18a, 18b, 23a, and 23b possessed
strong cytotoxicity, and the activity of the silyl ether 18a was
comparable to that of daunomycin. In agreement with our
working hypothesis, it is assumed that the comparatively good
efficacy of these nucleoside-leinamycin analogues is attributed
to the formation of base pairs with DNA.
a Reagents: (a) Ph3PCHCOSPh (1.3 equiv), toluene, room temperature,
48 h, 81%; (b) Et3N (2.1 equiv), H2S, 1,4-dioxane, room temperature, 2 h;
(c) K3[Fe(CN)6] (1.5 equiv), 1,4-dioxane/water, room temperature, 14 h,
73% (b+c); (d) dimethyldioxirane (1.0 equiv), acetone, room temperature,
2 h, 95%.
carrying an active ester, gave the R,â-unsaturated thioesters with
E-configuration (8 and 12, respectively) in a stereoselective
manner (Schemes 3 and 4). Thiolysis of 8 and 12 with the SH-
ion generated from hydrogen sulfide with triethylamine pro-
ceeded with conjugate addition and subsequent ester hydrolysis,
and the resulting â-mercaptothiolic acid intermediates were
oxidized, without isolation, with potassium hexacyanoferrate-
(III) into the dithiolanones 9 and 13, respectively. Th end
products (10 and 14) of these syntheses were obtained by
dimethyldioxirane oxidation.

5628 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18
Scheme 5. Reactions with Uridinea
Brief Articles
a Reagents: (a) Dess-Martin periodinane (1.5 equiv), CH2Cl2, 0 °C/room temperature, 1.5 h; (b) Ph3PCHCOSPh (1.4 equiv), 1,4-dioxan, room temperature,
22 h, 79% (a+b); (c) Et3N (2.1 equiv), H2S, 1,4-dioxane, room temperature, 2 h; (d) K3[Fe(CN)6] (1.5 equiv), 1,4-dioxane/water, room temperature, 16 h,
63% (c+d); (e) trifluoroacetic acid:H2O:THF 1:1:4, 0 °C, 6 h, 94%; (f) dimethyldioxirane, acetone, room temperature, 2 h, 96%, 95%.
Scheme 6. Reactions with Thymidinea
a Reagents: (a) Dess-Martin periodinane (1.5 equiv), CH2Cl2, 0 °C/room temperature, 1.5 h; (b) Ph3PCHCOSPh (1.4 equiv), 1,4-dioxane, room temperature,
22 h, 74% (a+b); (c) Et3N (2.1 equiv), H2S, 1,4-dioxane, room temperature, 2 h; (d) K3[Fe(CN)6] (1.5 equiv), 1,4-dioxane/water, room temperature, 15 h,
65% (c+d); (e) trifluoroacetic acid:H2O:THF 1:1:4, 0 °C, 6 h, 95%; (f) dimethyldioxirane, acetone, room temperature, 2 h, 94%, 95%.
Scheme 7. Synthesis of an Improved Open Chain Analoguea
a Reagents: (a) n-buthyllithium (1.0 equiv), THF, -10 °C, 15 min, Cu(I)I‚0.75Me2S (1.1 equiv), THF, -10 °C, 45 min; (b) Me3SiI (1.0 equiv), THF,
-78 °C, 10 min, acrolein (1.0 equiv), THF, -78 °C, -30 °C, 2.5 h, 42% (a+b); (c) Ph3PCHCOSPh (1.25 equiv), 1,4-dioxan, room temperature, 16 h, 75%;
(d) Et3N (2.1 equiv), H2S, 1,4-dioxane, room temperature, 2 h; (e) K3[Fe(CN)6] (1.5 equiv), 1,4-dioxane/water, room temperature, 17 h, 62% (d+e); (f)
dimethyldioxirane, acetone, room temperature, 2 h, 98%.
The cytotoxicity data of our compounds was also investigated
in relation with their liphophilic character. The logarithmic form
of the octanol/water distribution coefficient (CLogP) can be
approached theoretically, and this is extensively used for the
characterization of water solubility and membrane transport.
Data that came out of our studies are collected in Table 1, which

Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18 5629
H-6), 9.16 (NH). MS: calcd for C23H40O7N2S2Si2Na [M + Na]+
599.84, found 599.80. Mp 51-53 °C. Anal. (C23H40O7N2S2Si2) C,
H, N.
Table 1. Mean Cytotoxicities of Leinamycin Antibiotic Analogues
toward Human Cancer Cellsa
cytotoxicity
1-((2′R,4′S,5′S)-4′-(tert-Butyldimethylsilyloxy)-5′-((S)-[5′′-(2′′,5′′-
dioxo-1′′,2′′-dithiolan-3′′-yl)]-tetrahydrofuran-2′-yl]-5-methylpy-
rimidine-2,4(1H,3H)-dione (23b). To a solution of 23a (222 mg,
0.50 mmol) in dry acetone (25 mL) was added a dimethyldioxirane
solution (6.25 mL, C ) 0.080 mol/L, 1.0 equiv), and the mixture
was stirred at room temperature for 2 h. Evaporation gave 23b (216
mg, 94% yield), as a pale yellow solid, TLC: Rf 0.33 (D: 8:2
hexanes-EtOAc). 1H NMR (400 MHz, CDCl3) δ 0.17 (6H, s, Si-
(CH3)2), 0.89 (9H, s, C(CH3)3), 1.89 (3H, s, C(CH3)), 2.32 (2H, m,
H-3′), 3.14 (2H, d, J ) 8 Hz, H-4′′), 3.25 (1H, m, H-3′′), 4.10
(1H, m, H-4′), 4.59 (1H, m, H-5′), 6.13 (1H, dt (restricted rotation),
H-2′), 7.39 (1H, d, J ) 4 Hz, H-6), 8.44 (NH). MS: calcd for
C18H29S2O6N2Si [M + H]+ 461.73, found 461.76. Mp 54-56 °C.
Anal. (C18H28S2O6N2Si) C, H, N.
a
compound
IC50
IC50a (+EtSHb)
CLogP
daunomycin
9
10
13
14
18a
18b
19a
19b
23a
23b
24a
24b
28a
28b
2.96
-
-1.621
3.607
1.875
2.338
0.634
5.397
3.694
-1.449
-3.152
2.766
257.7
68.43
35.93
18.15
10.04
3.68
62.23
50.71
n.d.
43.12
298.8
118.7
123.7
62.88
65.54
24.75
16.87
12.60
7.84
2.67
20.72
7.01
16.69
6.61
54.62
29.69
20.11
8.33
1.063
-0.615
-2.318
2.831
5-(5′-(Tetrahydro-2H-pyran-2′-yloxy)pent-3′-ynyl)-1,2-dithi-
olan-3-one-1-oxide (28b). To a solution of 28a (70 mg, 0.245
mmol) in acetone (5 mL) was added a dimethyldioxirane solution
(3.65 mL, C ) 0.067 mol/L, 1.0 equiv), and the mixture was stirred
at room temperature for 2 h. Following concentration, the product
28b (73 mg, 98% yield) was isolated as a yellow syrup, TLC: Rf
1.009
a Cytoxicity values are micromolar concentrations (µM) corresponding
to 50% growth inhibition. b Ethanethiol.
indicate that in the case of the pair of compounds 23a/24a, 23b/
24b, 18a/19a, and 18b/19b carrying the silyl-protecting group
and the free hydroxyl, respectively, the cytotoxicity of the
lipophilic silyl compounds is higher than that of the respective
pair with a negative CLogP value. Compound 28b, which carries
a triple bond analogue of the molecular fragment of leinamycin
responsible for the DNA cleaving effect, is also a comparatively
active member of the series.
The cytotoxicity of simple leinamycin analogues has not been
extensively investigated. The results presented here demonstrate
that some derivatives of leinamycin with very simplified
structures, such as the dithiolanone-S-oxides, possess compara-
tive efficacy. Therefore further investigations of related com-
pounds may be worthwile. For this purpose, noncomplicated,
convenient synthetic procedures such as that described in this
paper can be extended to additional aldehydes. It is believed
that we have also succeeded in proving the cytotoxicity-
enhancing properties of silyl ethers, first reported by Padron et
al.,22 by using completely different structures, and this encour-
ages further systematic studies on the topic.
1
0.15 (C: 9:1 hexanes-EtOAc). H NMR (400 MHz, CDCl3) δ
1.54-1.75 (6H, m, THP), 2.00-2.12 (2H, m, H-1′), 2.45-2.51
(2H, s, H-2′), 2.68-2.76 and 3.04-3.12 (2H, dd, H-4), 3.51-3.55
(2H, m, THP), 3.70-3.87 (2H, m, H-5′), 4.16-4.33 (1H, q, H-5),
4.74 (1H, t, THP). MS: calcd for C13H18O4S2Na [M + Na]+ 325.04,
found. 325.01. Anal. Calcd for (C13H18O4S2 C) C, H, N.
Acknowledgment. This work was supported by the Hungar-
ian Academy of Sciences and the National Scientific Research
Found Grants No.: OTKA 42512 and RET-06/2004.
Supporting Information Available: Experimental procedures
and characterization data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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JM060471H