LeaVing Groups
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 21 6723
(11) Kisselev, A. F.; Callard, A.; Goldberg, A. L. Importance of the
Different Proteolytic Activities of the Proteasome and the Efficacy of
the Inhibitors Varies with the Protein Substrate. J. Biol. Chem. 2006,
281, 8582–8590.
(12) Bross, P. F.; Kane, R.; Farrell, A. T.; Abraham, S.; Benson, K.; Brower,
M. E.; Bradley, S.; Gobburu, J. V.; Goheer, A.; Lee, S.-L.; Leighton,
J.; Liang, C. Y.; Lostritto, R. T.; McGuinn, W. D.; Morse, D. E.;
Rahman, A.; Rosario, L. A.; Verbois, S. L.; Williams, G.; Wang, Y.-
C.; Pazdur, R. Approval Summary for Bortezomib for Injection in
the Treatment of Multiple Myeloma. Clin. Cancer Res. 2004, 10,
3954–3964.
(13) Richarson, P. G.; Barlogie, B.; Berenson, J.; Singhal, S.; Jagannath,
S.; Irwin, D.; Rajkumar, S. V.; Srkalovic, G.; Alsina, M.; Alexanian,
R.; Seigel, D.; Orlowski, R. Z.; Kuter, D.; Limentani, S. A.; Lee, S.;
Hideshima, T.; Esseltine, D. L.; Kauffman, M.; Adams, J.; Schenkein,
D. P.; Anderson, K. C. A Phase 2 Study of Bortezomib in Relapsed,
Refractory Myeloma. N. Engl. J. Med. 2003, 348, 2609–2617.
(14) Suh, K. S.; Goy, A. Bortezomib in Mantle Cell Lymphoma. Future
Oncol. 2008, 4, 149–168.
(15) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.; Jensen,
P. R.; Fenical, W. Salinosporamide A: A Highly Cytotoxic Proteasome
Inhibitor from a Novel Microbial Source, a Marine Bacterium of the
New Genus Salinospora. Angew.Chem. Int. Ed. 2003, 42, 355–357.
(16) Omura, S.; Matsuzaki, K.; Fujimoto, T.; Kosuge, K.; Furuya, T.; Fujita,
S.; Nakagawa, A. Structure of Lactacystin, a New Microbial Metabolite
Which Induces Differentation of Neuroblastoma Cells. J. Antibiot.
1991, 44, 117–118.
(17) Corey, E. J.; Li, W. Z. Total Synthesis and Biological Activity of
Lactacystin, Omuralide, and Analogs. Chem. Pharm. Bull. 1999, 47,
1–10.
(18) Dick, L. R.; Cruikshank, A. A.; Grenier, L.; Melandri, F. D.; Nunes,
S. L.; Stein, R. L. Mechanistic Studies on the Inactivation of the
Proteasome by Lactacystin. J. Biol. Chem. 1996, 271, 7273–7276.
(19) Shah, I. M.; Lees, K. R.; Pien, C. P.; Elliot, P. J. Early Clinical
Experience with the Novel Proteasome Inhibitor PS-519. Br. J. Clin.
Pharmacol. 2002, 54, 269–276.
(20) Williams, P. G.; Buchanan, G. O.; Feling, R. H.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. New Cytotoxic Salinosporamides from the
Marine Actinomycete Salinispora tropica. J. Org. Chem. 2005, 70,
6196–6203.
(21) Macherla, V. R.; Mitchell, S. S.; Manam, R. R.; Reed, K.; Chao, T.-
H.; Nicholson, B.; Deyanat-Yazdi, G.; Mai, B.; Jensen, P. R.; Fenical,
W.; Neuteboom, S. T. C.; Lam, K. S.; Palladino, M. A.; Potts, B. C. M.
Structure-Activity Relationship Studies of Salinosporamide A (NPI-
0052), a Novel Marine Derived Proteasome Inhibitor. J. Med. Chem.
2005, 48, 3684–3687.
(22) Reed, K. A.; Manam, R. R.; Mitchell, S. S.; Xu, J.; Teisan, S.; Chao,
T.-H.; Deyanat-Yazdi, G.; Neuteboom, S. T. C.; Lam, K. S.; Potts,
B. C. M. Salinosporamides D-J from the Marine Actinomycete
Salinispora tropica, Bromosalinosporamide, and Thioester Derivatives
Are Potent Inhibitors of the 20S Proteasome. J. Nat. Prod. 2007, 70,
269–276.
(23) Chauhan, D.; Catley, L.; Li, G.; Podar, K.; Hideshima, T.; Velankar,
M.; Mitsiades, C.; Mitsiades, N.; Yasui, H.; Letai, A.; Ovaa, H.;
Berkers, C.; Nicholson, B.; Chao, T.-H.; Neuteboom, S. T. C.;
Richardson, P.; Palladino, M.; Anderson, K. C. A Novel Orally Active
Proteasome Inhibitor Induces Apoptosis in Multiple Myeloma Cells
with Mechanisms Distinct from Bortesomib. Cancer Cell 2005, 8, 407–
419.
(24) Cusack, J. C., Jr.; Liu, R.; Xia, L.; Chao, T.-H.; Pien, C.; Niu, W.;
Palombella, V. J.; Neuteboom, S. T.; Palladino, M. A. NPI-0052
Enhances Tumoricidal Response to Conventional Cancer Therapy in
a Colon Cancer Model. Clin. Cancer Res. 2006, 12, 6758–6764.
(25) Ruiz, S.; Krupnik, Y.; Keating, M.; Chandra, J.; Palladino, M.;
McConkey, D. The Proteasome Inhibitor NPI-0052 Is a More Effective
Inducer of Apoptosis Than Bortezomib in Lymphocytes from Patients
with Chronic Lymphocytic Leukemia (CLL). Mol. Cancer Ther. 2006,
5, 1836–1843.
by the Obligate Marine Actinomycete Salinispora tropica. J. Antibiot.
2007, 60, 13–19.
(30) Reddy, L. R.; Reddy, B. V. S.; Corey, E. J. Efficient Method for
Selective Introduction of Substituents as C(5) of Isoleucine and Other
R-Amino Acids. Org. Lett. 2006, 8, 2819–2821.
(31) Moody, C. J.; Hunt, P. A.; Smith, C. Iodocyclisation of N-Allyl Ureas;
A Route to Imidazolin-2-ones. ARKIVOC 2000, (v), 698–706.
(32) We hypothesized that the DAST was reacting with secondary alcohol
(C-5) and then undergoing either nucleophilic addition to the cyclo-
hexene ring (C-5 (R)) or degradation (C-5 (S)). Thus, various protecting
group strategies (e.g., TMS, TES, or oxidation) were used on 6 and
12 to obtain the C-5OH protected derivative of 12, but in all cases,
either a degradant formed or deprotection occurred when DAST or
AgF was used. We did not target the total synthesis of a C-5OH-
protected derivative of 9.
(33) Suenaga, T.; Schutz, C.; Nakata, T. A Real Time Reaction Monitoring
Using Fluorescent Dansyl Group as a Solid-Phase Leaving Group.
Tetrahedron Lett. 2003, 44, 5799–5801.
(34) Denora, N.; Potts, B. C. M.; Stella, V. J. A Mechanistic and Kinetic
Study of the ꢀ-lactone Hydrolysis of Salinosporamide A (NPI-0052),
a Novel Proteasome Inhibitor. J. Pharm. Sci. 2007, 96, 2037–2047.
(35) Djuric, S. W.; Garland, R. B.; Nysted, L. N.; Pappo, R.; Plume, G.;
Swenton, L. Sythesis of 5-Fluoroprostacyclin. J. Org. Chem. 1987,
52, 978–990.
(36) Toscano, L.; Fioriello, G.; Silingardi, S.; Inglesi, M. Preparation of
(8S)-8-Fluoroerythronolide A and (8S)-8-Fluoroerythronolide B, Po-
tential Substrates for the Biological Synthesis of New Macrolide
Antibiotics. Tetrahedron 1984, 40, 2177–2181.
(37) Stadler, M.; Bitzer, J.; Mayer-Bartschmid, A.; Muller, H.; Benet-
Buchholz, J.; Gantner, F.; Tichy, H.-V.; Reinemer, P.; Bacon, K. B.
Cinnabaramides A-G: Analogs of Lactacystin and Salinosporamide
from a Terrestrial Streptomycete. J. Nat. Prod. 2007, 70, 246–252.
(38) It is conceivable that the “irreversible inhibition” by LG analogues
could be the result of a stable covalent bond between the inhibitor
and the proteasome borne from direct alkylation via the chlorethyl
group (as an alternative to or in addition to the covalent ester bond to
Thr1Oγ). However, there was no eVidence of any direct alkylation
product in the crystal structure of 1 with the 20S proteasome; only
the intramolecular chloride displacement product (cyclic ether end
product Ib′) was observed.26 Thus, there is little evidence to support
the hypothesis that the longer duration of proteasome inhibition in
the case of 1 (or other analogues in the LG family) results from direct
alkylation of proteasome amino acid(s) by the chloroethyl group.
Moreover, direct reactions of 1 or closely related compounds with
nucleophiles that may mimic amino acid side chains, including primary
alcohols, water or hydroxide, thiols, and amines, have resulted in
minimal or no direct displacement of chloride. Reaction of 1 with
nucleophiles, hydroxide or water,21 MeOH,20 and thiol22 initially
cleaved the ꢀ-lactone ring and produced carboxylic acid, methylester
and thioesters, respectively, which were further converted to form the
corresponding cyclic ether ring product by intramolecular displacement
of chloride with C-3 OH with no report on direct displacement of
chloride with those of nucleophiles used in the reaction. Reaction of
a synthetic analogue of 1 with primary amine (benzylamine) also
produced similar products with no report on direct replacement of
chloride.39 In one instance, trace amounts (2%) of the disubstituted
product of ꢀ-lactone cleavage and chloride displacement were detected
in the reaction mixture by LC-MS when compound 1 was reacted
with benzene thiol. Reaction of 1 with triethylamine at 40 °C (our
own findings) or NaOH20 gave decarboxylation (by ꢀ-elimination of
carboxylate) products with no reports on displacement of chloride.
Reaction of iodosalinosporamide (6) with NaOH gave 12 as a minor
byproduct;21 we note that 6 is a better substrate for halogen
displacement than 1.
(39) Reddy, L. R.; Fournier, J.-F.; Reddy, B. V. S.; Corey, E. J. An Efficient,
Stereocontrolled Synthesis of a Potent Omuralide-Salinosporin Hybrid
for Selective Proteasome Inhibition. J. Am. Chem. Soc. 2005, 127,
8974–8976.
(40) Morrison, J. F.; Walsh, C. T. The Behavior and Significance of Slow-
(26) Groll, M.; Huber, R.; Potts, B. C. M. Crystal Structure of Salino-
sporamide A (NPI-0052) and B (NPI-0047) in Complex with the 20S
Protesome Reveal Important Consequences of ꢀ-Lactone Ring Opening
and a Mechanism for Irreversible Binding. J. Am. Chem. Soc. 2006,
128, 5136–5141.
(27) Fenteany, G.; Standaert, R. F.; Lane, W. S.; Choi, S.; Corey, E. J.;
Schreiber, S. L. Inhibition of Proteasome Activities and Subunit-
Specific Amino-Terminal Threonine Modification by Lactacystin.
Science 1995, 268, 726–731.
Binding Inhibitors. AdV. Enzymol. 1988, 61, 201–301.
(41) Jaramillo, P.; Domingo, L. R.; Perez, P. Towards an Intrinsic
Nucleofugality Scale: The Leaving group (LG) Ability in CH3LG
Model System. Chem. Phys. Lett. 2006, 420, 95–99.
(42) The ꢀ-lactone hydrolysis product of 4 did not inhibit the CT-L, T-L,
or C-L activities of rabbit 20S proteasomes at the highest concentra-
tions tested (IC50 > 20 µM; unpublished result).
(43) Eustaquio, A. S.; Moore, B. S. Mutasynthesis of Fluorosalinospora-
mide, a Potent and Reversible Inhibitor of a Proteasome. Angew.
Chem., Int. Ed. 2008, 47, 3936-3938.
(44) O’Hagan, D.; Rzepa, H. S. Some Influences of Fluorine in Bioorganic
Chemistry. Chem. Commun. 1997, 645–652.
(28) Ling, T.; Macherla, V. R.; Manam, R. R.; McArthur, K. A.; Potts,
B. C. M. Enantioselective Total Synthesis of (-)-Salinosporamide A
(NPI-0052). Org. Lett. 2007, 9, 2289–2292.
(29) Lam, K. S.; Tsueng, G.; McArthur, K. A.; Mitchell, S. S.; Potts,
(45) Olsen, J. A.; Banner, D. W.; Seiler, P.; Wagner, B.; Tschopp, T.; Obst-
Sander, U.; Kansy, M.; Muller, K.; Diederich, F. Fluorine Interactions
B. C. M. Effects of Halogens on the Production of Salinosporamides