Synthesis and biological activity of sarcodictyins

Full text of DOI:10.1002/(SICI)1521-3773(19980605)37:10<1418::AID-ANIE1418>3.0.CO;2-5

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[11] E. Taskinen, M. Anttila, Tetrahedron 1977, 33, 2423.
[12] Compound 12 is formed as a mixture of two isomers that rapidly
equilibrate under the reaction conditions. The trans isomer with
methoxy groups in axial positions crystallizes preferentially from the
reaction mixture and can be obtained pure in greater than 90% yield
with only 10 4 mol% catalyst.
Synthesis and Biological Activity of
Sarcodictyins**
K. C. Nicolaou,* Sanghee Kim, Jeffrey Pfefferkorn,
Jinyou Xu, Takashi Ohshima, Seijiro Hosokawa,
Dionisios Vourloumis, and Tianhu Li
[13] W. Reppe, Justus Liebigs Ann. Chem. 1955, 596, 1 (see pages 62
and 64).
[14] These catalysts are also able to catalyze the addition of water and
carboxylic acids to alkynes. A preliminary report of this work appears
in reference [7].
Isolated from certain species of soft corals, the sarcodictyins
(1, 2),[1, 2] eleutherobin (3),[3, 4] and the eleuthosides (4, 5)[5]
have become important synthetic targets because of their
novel molecular architectures, biological activities, and me-
dicinal potential (Figure 1). Of special interest is their taxol-
like mechanism[6] of action, which involves tubulin polymeri-
[15] Generated from [LAu(NO3)] and ten equivalents of BF3 ´ OEt2. The
nitrates were synthesized from the known chlorides through meta-
thesis with AgNO3. For a typical procedure, see L. Malatesta, L.
Naldini, G. Simonetta, F. Cariati, Coord. Chem. Rev. 1966, 1, 255.
[16] Nucleophilic carbenes such as 1,3,4-triphenyl-4,5-dihydro-1,2,4-tria-
zol-(1H)-ylidene are also suitable ligands. We prepared the corre-
sponding gold(i) chloride complex by treating the isolated carbene
with dimethylsulfidegold(i) chloride. This carbenegold(i) complex
proved to be 3.5 times more active than triphenylphosphanegold(i)
chloride. Unfortunately we did not succeed in the preparation of
either the carbenegold nitrate or the carbenegold methyl complexes.
[17] Amazingly, even HBF4 is quickly hydrolyzed to trimethylborate under
the reaction conditions.
O
O
N
O
N
O
H
H
N
H
8
N
6
5
O
10
O
1
OR1
[18] The same turnover rate (700 h 1) is observed when the catalyst is
OH
CO2R
3
‡
H
generated from the oxonium salt [(Ph3PAu)3O BF4 ] and BF3 ´ OEt2.
O
OAc
[19] All ab initio calculations were performed with the TURBOMOLE
program package. For an overview of TURBOMOLE, see R.
Ahlrichs, M. von Arnim in Methods and Techniques in Computational
Chemistry: METECC-95 (Eds.: E. Clementi, G. Corongiu) STEF,
Cagliari, 1995, P. 509 ± 554. Geometries were calculated at the RI-DFT
level (K. Eichkorn, O. Treutler, H. Ihm, M. Häser, R. Ahlrichs; Chem.
Phys. Lett. 1995, 242, 652) with the Becke ± Perdew functional and the
TURBOMOLE SV(P) basis sets (K. Eichkorn, F. Weigend, O.
Treutler, R. Ahlrichs, Theor. Chem. Acc. 1997, 97, 119). For gold, the
60-mwb relativistic pseudopotential was utilized (D. Andrae, U.
Haeussermann, M. Dolg, H. Stoll, H. Preuss, Theor. Chim. Acta 1990,
77, 123). Energies were calculated at the MP2 level with TZVP basis
sets through the recently developed RI-MP2 implementation (F.
Weigend, M. Häser, Theor. Chem. Acc. 1997, 97, 331).
15
OR2
O
OR3
3: R1 = Me, R2 = H,
1:R = Me
2:R = Et
R3 = H
R3 = H
R3 =Ac
1
2
4:
R = H, R = Ac,
5: R1 = H, R2 = H,
Figure 1. Structures of sarcodictyins A (1) and B (2), eleutherobin (3), and
eleuthosides A (4) and B (5).
zation and microtubule stabilization and results in tumor-cell
death. The combination of the scarcity and the appealing
biological activity of these materials prompted us to initiate a
program directed at their chemical synthesis. We recently
disclosed the first total syntheses of sarcodictyin A (1)[7] and
eleutherobin (3).[8] Here we report the first synthesis of
sarcodictyin B (2), the construction of a sarcodictyin library,
and the tubulin-polymerization and cytotoxic properties of
members of that library, including their action against a
number of taxol-resistant tumor-cell lines.
[20] The peaks coalesce at 408C to a single broad peak at d ˆ 32. Above
208C this peak becomes narrower, and at 08C only the sharp signal
of [Ph3PAuCl] remains at d ˆ 31. The independently synthesized
triphenylphosphanegold(i) methanesulfonate (from triphenylphos-
phanegold(i) iodide and silver methanesulfonate) shows a broadened
peak at d ˆ 27 (31P NMR in CD2Cl2 at 408C).
[21] Coordination of methanol with 18 to form the T-shaped complex 19
disturbs the structure only slightly. The angle between phosphorus,
gold, and the center of the triple bond changes from 1798 in 18 to 1758
in 19. The Au ± O bond in 19 is very long (3.7 Š compared to 2.1 Š for
a Au ± O single bond), and the P-Au-O angle is 838.
To conveniently access a sarcodictyin library, an improved
method for their construction was devised (Scheme 1), which
[22] A. Tamaki, J. K. Kochi, J. Organomet. Chem. 1973, 61, 441.
[23] The stereochemistry was determined by X-ray crystallography.
Crystallographic data (excluding structure factors) for the structure
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC-100957. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax:
(‡44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
[*] Prof. Dr. K. C. Nicolaou, Dr. S. Kim, J. Pfefferkorn, Dr. J. Xu,
Dr. T. Ohshima, Dr. S. Hosokawa, Dr. D. Vourloumis, Dr. T. Li
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (‡1)619-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] This work was supported by The Skaggs Institute for Chemical
Biology, the U.S. National Institutes of Health, Novartis, and the CaP
CURE Foundation, and by fellowships from Novartis (D.V.), the
Japanese Society for the Promotion of Science for Young Scientists
(S.H.), and the U.S. Department of Defense (J.P.).
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relies on the use of more effective protecting groups (6) and
hydrogenation catalysts (8 !9), and includes a number of
alternative esterification protocols. Thus, the previously
synthesized alcohol 6[8] was protected as a TIPS ether (6!7,
79%; for abbreviations, see the scheme legend) prior to ring
closure (LiHMDS, 208C) and Dess ± Martin[9] oxidation to
afford ten-membered ring enynone 8 (89% over two steps).
Desilylation of 8 with 3HF ´ Et3N (78%) followed by selective
hydrogenation[10] in the presence of [Rh(nbd)(dppb)]BF4 led
through ring closure of a short-lived dihydroxydienone to the
tricyclic skeleton. The resulting intermediate was converted to
its methoxy acetal 9 (80% over two steps), which served as a
common intermediate for the total synthesis of sarcodictyin B
(2) and the construction of a sarcodictyin library. Three
methods of esterification used in the generation of the library
are exemplified in Scheme 1 by the syntheses of 11, 14, and 15.
Specifically, treatment of alcohol 9 with mixed anhydride 10 in
the presence of DMAP resulted in the formation of urocanic
ester derivative 11 in 83% yield. Subsequent cleavage of the
silyl ether group with TBAF (100% yield) followed by a series
of standard transformations (Dess ± Martin and NaClO2
oxidations and diazoalkane esterification) led to the isolation
of methyl and ethyl esters 12 and 13 (88 and 90%, relatively,
over three steps). The natural sarcodictyins A (1) and B (2)
were obtained after acidic hydrolysis with 10-camphorsulfonic
acid in CH2Cl2/H2O (80 and 86%, respectively). In a second
approach, treatment of 9 with acetic anhydride in the
presence of DMAP provided acetate 14 (95% yield), which
was in turn transformed into sarcodictyin A analogue 16 by
the previously described sequence.[7] Finally, reaction of 9 with
(E)-3-(2-methyloxazol-4-yl)propenoic acid in the presence of
DCC and DMAP gave a number of other side-chain
analogues (Table 1).
OTES
OTES
OTES
H
H
OTES
H
H
b, c
CHO
OR
O
OTIPS
8
6: R = H
a
7: R = TIPS
d–f
O
O
H
OH
R
H
m or n
O
O
OMe
OMe
H
H
OTIPS
OTIPS
9
R
R
14:
15:
= Me
=
O
O
N
g
tBu
O
N
h–k
10
O
N
O
N
N
O
O
H
O
O
R
H
H
OMe
OH
H
O
11
OMe
CO2R
R
16: R = Me,
17: R = Et,
= Me
R
=
h–k
O
N
O
O
The synthetic sarcodictyins were evaluated for tubulin-
polymerization and cytotoxic properties, and were compared
with taxol and epothilones A and B (Table 1). The colori-
metric-filtration assay for tubulin polymerization[11, 12] was
utilized to determine the tubulin effects of sarcodictyins 1, 2,
11 ± 13, and 16 ± 25. They exhibited varying degrees of
polymerizing properties ranging from 4.0 to 85% (for
comparison: taxol, 65%; epothilone A, 72%; epothilone B,
97%). Cytotoxicity studies were conducted with the
parental ovarian carcinoma cell line 1A9 and the taxol-
resistant tumor-cell lines PTX10 and PTX22[13] derived from
1A9. The observed activity of the synthetic compounds
proved to be highly dependent upon their precise structures
(Table 1).
A number of conclusions can be drawn from these studies
with respect to structure ± activity relationships (SARs). The
C8 side chain is crucial for both tubulin-polymerization and
cytotoxic properties, as shown by a comparison of compounds
13 and 16. Reduction of the ester group at C15 to a primary
alcohol (11) resulted in a decrease in activity. The sarcodictyin
pharmacophore appears in fact to be rather sensitive to
modification at C15 (reduction), as is apparent from the
properties of compounds 21 ± 25. An increase in the size of the
alkyl group on the C4 acetal seems to have only a small effect
on the biological activity of the compounds (see 1, 12, 18, and
19).
N
N
O
O
H
H
H
N
N
O
O
l
OMe
OH
H
CO2R
CO2R
1: R = Me: sarcodictyin A
2: R = Et : sarcodictyin B
12: R = Me
13: R = Et
Scheme 1. Syntheses of sarcodictyins A (1) and
B (2) and various
analogues. a) TIPSOTf (5.0 equiv), iPr2NEt (10 equiv), CH2Cl2, 788C,
1 h, 79%; b) LiHMDS (2.0 equiv), THF, 208C, 20 min; c) Dess ± Martin
periodinane (2.0 equiv), pyridine (6.0 equiv), NaHCO3 (6.0 equiv), CH2Cl2,
08C, 1 h, 89% over two steps; d) 3HF ´ Et3N (5.0 equiv), THF, 258C, 1.5 h,
78%; e) [Rh(nbd)(dppb)]BF4 (0.05 equiv), H2, acetone, 258C, 10 min;
f) PPTS (0.5 equiv), MeOH, 258C, 10 min, 80% over two steps; g) 10
(5.0 equiv), Et3N (20 equiv), DMAP (2.0 equiv), CH2Cl2, 258C, 48 h, 83%;
h) TBAF (2.0 equiv), THF, 258C, 2 h, 100%; i) Dess ± Martin periodinane
(2.5 equiv), NaHCO3 (10 equiv), CH2Cl2, 258C, 0.5 h; j) NaClO2
(6.0 equiv), NaH2PO4 (3.0 equiv), 2-methyl-2-butene (50 equiv), THF,
tBuOH, H2O; k) CH2N2 or CH3CHN2, Et2O, 88% (12) and 90% (13)
over three steps; l) CSA (2.0 equiv), CH2Cl2:H2O (10:1), 258C, 48 h, 80 (1)
and 86% (2); m) Ac2O (3.0 equiv), Et3N (5.0 equiv), DMAP (1.0 equiv),
CH2Cl2, 258C, 1 h, 95%; n) DCC (2.0 equiv), (E)-3-(2-methyloxazole-4-
yl)propenoic acid (1.3 equiv), DMAP (0.5 equiv), CH2Cl2, 258C, 36 h,
86%. CSA ˆ 10-camphorsulfonic acid, DCC ˆ 1,3-dicyclohexylcarbodii-
mide, DMAP ˆ 4-(dimethylamino)pyridine, dppb ˆ 1,4-bis(diphenylphos-
phanyl)butane, LiHMDS ˆ lithium hexamethyldisilazanide, nbd ˆ 2,5-nor-
bornadiene, PPTS ˆ pyridinium p-toluenesulfonate, TBAF ˆ tetra-n-butyl-
ammonium fluoride, TIPSOTf ˆ trisisopropylsilyl trifluoromethane-
sulfonate.
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Table 1. Tubulin-polymerizing and cytotoxic characteristics of the sarcodictyins.
Inhibition of cancer-cell growth (IC50 [nm])
Compound
Induction of
tubulin poly-
merization [%]
1A9
1A9PTX10
1A9PTX22
taxol
65.0
72.7
97.0
67.0
71.0
2.0
2.0
0.04
340
2.0
50
1.9
0.035
140
160
40
4.0
0.04
360
epothilone A
epothilone B
sarcodictyin A
sarcodictyin B
1
2
80
O
N
12
18[c]
19[d]
R ˆ Me
R ˆ Et
72.0
85.0
79.0
70
110
170
3.6
13
> 2000
84
160
130
O
H
N
R ˆ nPr
O
OR
H
CO2Me
O
N
O
O
O
O
H
H
N
13
46.0
2.0
0.6
6.0
O
OMe
CO2Et
O
H
H
16
4.0
4.0
> 2000
> 2000
510
1300
> 2000
O
OMe
CO2Me
O
O
H
H
N
17
800
385
O
OMe
CO2Et
O
N
H
H
N
20[e]
52.0
1700
1800
O
OMe
CO2Me
O
11
R ˆ OH
37.5
27.4
37.2
34.1
47.0
37.0
800
1850
1050
> 2000
> 2000
> 2000
> 2000
> 2000
> 2000
> 2000
> 2000
> 2000
> 2000
> 2000
1620
> 2000
1800
N
O
21[f]
22[g]
23[h]
24[i]
25[j]
R ˆ F
H
H
N
R ˆ OAc
R ˆ OBz
R ˆ N3
O
OMe
R
R ˆ OCONHPh
> 2000
[a] Tubulin-polymerization measurements were carried out at 378C as described,[11, 12] apart from adjustments in the concentration of active agents (100 mm)
and incubation time (90 min). [b] The cytotoxicity investigations were carried out as described.[12, 13] [c] From sarcodictyin A (1) by treatment with CSA/
EtOH in CH2Cl2 (98%). [d] From sarcodictyin A (1) by treatment with CSA/nPrOH in CH2Cl2 (90%). [e] By-product from overreduction of the triple bond
and subsequent acetalization. [f] From 11 by treatment with DAST (99%). [g] From 11 by treatment with Ac2O, Et3N, and DMAP (100%). [h] From 11 by
treatment with BzCl, Et3N, and DMAP (95%). [i] From 11 by treatment with (PhO)2PON3, DEAD, and Ph3P (74%). [j] From 11 by treatment with PhNCO
and Et3N (95%). Bz ˆ benzyl, CSA ˆ 10-camphorsulfonic acid, DASTˆ (diethylamino)sulfur trifluoride, DEAD ˆ diethyl azodicarboxylate, DMAP ˆ 4-
(dimethylamino)pyridine.
The apparent inconsistency between tubulin-polymeriza-
tion activity and cytotoxicity for a number of these com-
pounds (e.g., 13, 17, 20) may be indicative of the availability
of an additional mechanism of action in some cases.
Indeed, inspection of the structures of sarcodictyins and
eleutherobins reveals their potential as alkylating agents
under acidic conditions (Figure 2), so they may be capable of
interacting with DNA and other cellular receptors. Experi-
ments directed toward confirming this hypothesis are in
progress.
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O
Cooperative Hairpin Dimers for Recognition of
DNA by Pyrrole ± Imidazole Polyamides**
N
Me
O
Me
Me
N
H
H
John W. Trauger, Eldon E. Baird, and Peter B. Dervan*
O
Nu
Small molecules which permeate cells and bind to specific
DNA sequences can potentially control the expression of
specific genes.[1, 2] Recently, a polyamide with eight hetero-
cyclic units which binds to a target site consisting of six base
pairs was shown to inhibit gene transcription in a cell
culture.[2] Polyamides that recognize longer DNA sequences
should provide more specific biological activity,[3] which could
be achieved by synthesizing larger polyamides.[4] However,
the upper limit of polyamide size with regard to efficient cell
permeation is not known.
R
Nu
Me
Me
Nu
Figure 2. Alkylating properties of sarcodictyins and eleutherobins.
The chemistry and biological activity presented here shows
the sarcodictyins to be a new class of potential anticancer
agents. Access to additional derivatives and closer investiga-
tion are now possible through the use of molecular design and
chemical synthesis. The first structure ± activity information
on sarcodictyins, reported here, should provide valuable
guidelines for further chemical and biological studies.[14]
Alternatively, a more biomimetic approach is to bind larger
DNA sequences while maintaining the size of the polyamide.
Natural transcription factors often bind large DNA sequences
by formation of cooperative protein dimers at adjacent half-
sites.[5] In cooperatively binding extended pyrrole ± imidazole
(Py ± Im) polyamide dimers, the two ligands can slip sideways
with respect to one another to allow recognition of other
sequences.[6] Polyamides containing the turn-specific g-amino-
butyric acid linker[7] adopt a hairpin conformation in which
the DNA binding sites are fully overlapped and the slipped-
motif option is precluded. Here we report a cooperative six-
ring extended hairpin polyamide which dimerizes to specif-
ically bind a predetermined sequence of ten base pairs.
As target site, we chose a sequence contained in the
regulatory region of the HIV-1 genome.[8] To design the ligand
we considered the polyamide ring-pairing rules,[9±13] the need
to incorporate b-alanine (b) to relax the ligand curvature,[6, 13]
and the preference of g-aminobutyric acid (g) for a hairpin-
turn conformation in polyamide ± DNA complexes.[6, 7a,e] This
analysis suggested that the six-ring polyamide having the core
sequence ImPybImPygImPy might bind the target sequence
5'-AGCAGCTGCT-3' by formation of a cooperative hairpin
dimer (Figure 1). To avoid a collision between the N-terminal
end of one ligand and the C-terminal end of the other in the
complex, the positively charged b-alaninedimethylaminopro-
plyamide C terminus used in standard polyamides was
replaced with the shorter, uncharged (CH2)2OH group (C2 ±
OH). The cationic turn residue (R)-2,4-diaminobutyric acid
Received: January 22, 1998 [Z11393IE]
German version: Angew. Chem. 1998, 110, 1484 ± 1487
Keywords: antitumor agents ´ sarcodictyins ´ structure ± ac-
tivity relationships ´ total synthesis ´ tubulin polymerizations
[1] a) M. D'Ambrosio, A. Guerriero, F. Pietra, Helv. Chim. Acta 1987, 70,
2019 ± 2027; b) ibid., 1988, 71, 964 ± 976.
[2] M. Ciomei, C. Albanese, W. Pastori, M. Grandi, F. Pietra, M.
D'Ambrosio, A. Guerriero, C. Battistini, Abstract 30, Proc. Amer.
Ass. Canc. Res. 1997, 38, 5.
[3] W.-H. Fenical, P. R. Jensen, T. Lindel (University of California), US-A
5,473,057, 1995 [Chem Abstr. 1996, 124, 194297z].
[4] (a) T. Lindel, P. R. Jensen, W. Fenical, B. H. Long, A. M. Casazza, J.
Carboni, C. R. Fairchild, J. Am. Chem. Soc. 1997, 119, 8744 ± 8745; (b)
B. H. Long, A. M. Casazza, J. Carboni, C. R. Fairchild, T. Lindel, P. R.
Jensen, W. Fenical, Cancer Res., submitted.
[5] S. Ketzinel, A. Rudi, M. Schleyer, Y. Benayahu, Y. Kashman, J. Nat.
Prod. 1987, 59, 873 ± 875.
[6] P. B. Schiff, J. Fant, S. B. Horwitz, Nature 1979, 277, 665 ± 667.
[7] K. C. Nicolaou, J. Y. Xu, S. Kim, T. Ohshima, S. Hosokawa, J.
Pfefferkorn, J. Am. Chem. Soc. 1997, 119, 11353 ± 11354.
[8] K. C. Nicolaou, F. van Delft, T. Oshima, D. Vourloumis, J.-Y. Xu, S.
Hosokawa, J. Pfefferkorn, S. Kim, T. Li, Angew. Chem. 1997, 109,
2630 ± 2634; Angew. Chem. Int. Ed. Engl. 1997, 36, 2520 ± 2524.
[9] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155 ± 4156.
[10] R. R. Schrock, J. Osborn, J. Am. Chem. Soc. 1976, 98, 2143 ± 2144.
[11] D. M. Bollag, P. A. McQueney, J. Zhu, O. Hensens, L. Koupal, J.
Liesch, M. Goetz, E. Lazarides, C. M. Woods, Cancer Res. 1995, 55,
2325 ± 2333.
[12] K. C. Nicolaou, D. Vourloumis, T. Li, N. Winssinger, Y. He, S.
Ninkovic, F. Sarabia, H. Vallberg, F. Roschangar, N. P. King, M. R. V.
Finlay, Z. Yang, T. Li, P. Giannakakou, P. Verdier-Pinard, E. Hamel,
Angew. Chem. 1997, 109, 2181 ± 2187; Angew. Chem. Int. Ed. Engl.
1997, 36, 2097 ± 2103.
[13] P. Giannakakou, D. L. Sackett, Y.-K. Kang, Z. Zhan, J. T. M. Buters,
M. S. Fojo, M. S. Poruchynsky, J. Biol. Chem. 1997, 272, 17118 ± 17125.
[14] For a recently reported total synthesis of the related natural product
eleutherobin, see a) X.-T. Chen, C. E. Gutteridge, S. K. Bhattacharya,
B. Zhou, T. R. R. Pettus, T. Hascall, S. J. Danishefsky, Angew. Chem.
1998, 110, 195 ± 197; Angew. Chem. Int. Ed. 1998, 37, 185 ± 187; b) X.-T.
Chen, B. Zhou, S. K. Bhattacharya, C. E. Gutteridge, T. R. R. Pettus,
S. J. Danishefsky, Angew. Chem. 1998, 110, 835 ± 838; Angew. Chem.
Int. Ed. 1998, 37, 789 ± 792.
((R)H Ng)[14] maintains the overall positive charge needed for
2
optimal solubility in water.
Polyamide ImPybImPy(R)H NgImPyC2-OH (1) was synthe-
2
sized by solid-phase methods[15] on glycine ± PAM resin,[16]
reductively cleaved from the solid support with LiBH4,[17]
[*] Prof. P. B. Dervan, J. W. Trauger, E. E. Baird
Arnold and Mabel Beckman Laboratories of Chemical Synthesis
California Institute of Technology
Pasadena, CA 91101 (USA)
Fax: (‡1)626-568-8824
E-mail: dervan@cco.caltech.edu
[**] We are grateful to the National Institutes of Health for support (GM-
27681), to the National Science Foundation and the Ralph M. Parsons
Foundation for predoctoral fellowships to J.W.T., and to the Howard
Hughes Medical Institute for a predoctoral fellowship to E.E.B.
Supporting information for this article is available on the WWW
under http://www.wiley-vch.de/home/angewandte/ or from the au-
thor.
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