Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-19
2004-01-06
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S336000, C549S337000
Reexamination Certificate
active
06673937
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates in general to anticancer agents, and more specifically to synthetic analogs of deoxypreussomerin, palmarumycin CP
1
and related naphthoquinone spiroketals, which exhibit antimitotic activity.
BACKGROUND OF THE INVENTION
The cell cycle consists of series of stages abbreviated G1- S - G2 - M. G1 stands for gap number 1; S for synthesis (DNA synthesis occurs); G2 for gap number 2 and M for mitosis or cell division. Control of cell division is very complex and involves regulation at a number of levels. In cancerous cells, the normal regulatory processes are somehow disrupted and cell growth is uncontrolled.
Tubulin is a protein that polymerizes into long chains or filaments that form microtubules. Microtubules are hollow fibers, which serve as kind of a skeletal system for living cells. Microtubules have the ability to shift through various formations, thus allowing the cell to undergo mitosis. The formation-shifting of microtubules is made possible by the flexibility of tubulin monomers, especially in the presence of agents/drugs and proteins that bind tubulin.
Interest in tubulin has increased recently because a natural substance (paclitaxel) found in the bark of the Pacific yew tree, was shown in clinical tests to be an effective treatment for a number of cancers including ovarian, breast, and lung. Paclitaxel prevents cell division by promoting the assembly of and inhibiting the disassembly of microtubules.
Cell cycle checkpoints are critical regulators of genome integrity and faithful cell replication. One of the main abnormalities in human tumors cells is the loss of the G1 phase checkpoint, which not only permits cellular replication but also encourages genomic instability. Consequently, enforcement of the G2/M checkpoint represents an attractive mode of action for new antineoplastic agents. G2/M progression is tightly regulated by several cellular macromolecules, including tubulins, and microtubule-associated proteins and motor proteins, such as kinesins and dynesins. An additional essential regulator is the maturation/M-phase promoting factor comprising Cdk1/cyclin B. Cdk1/cyclin B itself is regulated by a complex group of positive and negative regulating kinases. In mammalian cells, these include weel, mytt, cyclin activating kinase, Chk1 and cds1 kinases. In addition, Cdc25 phosphatases, which are also regulated by other kinases and phosphatases, are responsible for the activation of Cdk1.
Inhibitors of tubulin polymerization or depolymerization are widely available but only a few disrupters of other regulators of G2/M progression have been identified. For example, several small molecule inhibitors of Cdc25 that block G2/M progression have been identified, but those compounds also affect G1 transition (Tamura K, Rice RL, Wipf P and Lazo JS (1999) Dual G1 and G2/M phase inhibition by SC-&agr;&agr;&dgr;9, a combinatorially derived Cdc25 phosphatase inhibitor. Oncogene 18:6989-6996, Tamura K, Southwick EC, Kerns J, Rosi K, Carr BI, Wilcox C and Lazo JS (2000) Cdc25 inhibition and cell cycle arrest by a synthetic thioalkyl vitamin K analogue. Cancer Res 60:1317-1325). Others have recently isolated a novel mitotic blocker that appears to act as a specific inhibitor of a mitotic kinesin (Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL and Mitchison TJ (1999) Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286:971-974). Nonetheless, there continues to be a great need for pharmacologically distinct agents both to investigate the G2/M progression process and as new pharmacophores for drug design strategies.
The antifungal metabolites, preussomerins A-F, were identified in 1990 by Gloer and coworkers during the course of an investigation of chemical agents involved in interspecies competition among coprophilous (dung-colonizing) fungi. (Weber, H. A.; Baenziger, N. C.; Gloer, J. B.
J Am. Chem. Soc.
1990, 112, 6718). In addition to those early reports from
Preussia isomera
Cain samples, preussomerins were later also discovered in the endophytic fungus
Harmonerna dematioides
(Polish J. D.; Dombrowski, A. W.; Tsou, N. N.; Salituro, G. M.; Curotto, J. E.
Mycologia
1993, 85, 62). Other reports of an epoxy naphthalenediol spiroketal compound, bipendensin, have been published (Connolly, J. D. 4
th International Symposium and Pakistan-US. Binational Workshop on Natural Products Chemistry
, Karachi, Pakistan, January 1990 and Connolly, J. D.:
Structural elucidation of some natural products. In Studies in Natural Products Chemistry
, Vol 9. Ed., Atta-ur-Rahman, pp. 256-258, Elsevier Science Publishers B. V., Amsterdam, 1991). Bipendensin was isolated in very small amounts from wood samples of the African tree
Afzelia bipendensis
. A compound having the same gross structure as bipendensin was isolated in 1994 from an unidentified Coniothyium fungus collected from forest soil on West Borneo, and was named palmarumycin C
11
, (Krohn, K.; Michel, A.; Florke, U.; Aust, H.-J.; Draeger, S.; Schulz, B.
Liebigs Ann. Chem.
1994, 1099).
The pentacyclic palmarumycins are structurally unique natural products with both antifungal and antibacterial activities, but their antineoplastic effects are not well established. The naphthoquinone acetals, palmarumycins, diepoxins and deoxypreussomerins are structurally unique fungal metabolites with both antifungal and antibacterial activities, but their antiproliferative activity against malignant mammalian cells has not been extensively studied. (Wipf, P and June JK (1998) Total synthesis of palmarumycin CP1 and (±)-deoxypreussomerin A. J Org Chem 63:3530-3531: Schlingmann GRR, West LP, Milne CJ and Carter GT (1993) Diepoxins, novel fungal metabolites with antibiotic activity. Tetrahedron Lett 34:7225-7228: Krohn K, Michel A, Florke U, Aust H-J, Draeger S and Schulz B (1994) Palmarumycins C1-C6 from Coniothyrium: Isolation, structure elucidation, and biological activity. Liebigs Ann Chem 1994:1099-1108). Biological studies have been limited due to the extraordinary synthetic challenges associated with the extensive levels of oxygenation and the highly electrophilic functionality present in these spiroketal natural products.
Since its discovery in the early 1960s, the thioredoxin—thioredoxin reductase system has been the subject of intense pharmacological studies (Williams,C.H.
Eur.JBiochem.
2000, 267, 6101). The two redox active proteins have been isolated from many species, and their medical interest is based in part on their value as indicators of widespread diseases such as rheumatoid arthritis, AIDS, and cancer. The cytosolic 12 kDa thioredoxin-1 (Trx-1) is the major cellular protein disulfide reductase and its dithiol-disulfide active site cysteine pair (CXXC) serves as electron donor for enzymes such as ribonucleotide reductase, methionine sulfoxide reductase, and transcription factors including NF-&kgr;B and the Ref-1-dependent AP-1 (Arn r,E.S.J.; Holmgren,A.
Eur.JBiochem.
2000, 267, 6102). Therefore, thioredoxin-l is critical for cellular redox regulation, signaling, and regulation of protein function as well as defense against oxidative stress and control of growth and apoptosis. (Davis,W.; Ronai,Z.; Tew,K.D.
JPharm.Exp. Ther.
2001, 296, 1). Thioredoxin-1 acts in concert with the glutathione—glutathione reductase system but with a rate of reaction orders of magnitude faster,and lack of cytosolic mammalian thioredoxin is embryonically lethal. Eukaryotic thioredoxin reductases (TrxR) are 112-130 kDa, selenium-dependent dimeric flavoproteins that also reduce substrates such as hydroperoxides or vitamin C (Williams, C.H.; Arscott, L.D.; Miller,S.; Lennon,B.W.; Ludwig,M.L.; Wang,P.-F.; Veine,D.M.; Becker,K.; Schirmer,R.H.
Eur.JBiochem.
2000, 267,6110). These reductases contain redox-active selenylsulfide-selenolthiol active sites and are inhibited by aurothioglucose and auranofin (K; 4 nM). (Becker,K.; Gromer,S.; Schirmer,R.H.; Mller,S.
Eur.JBiochem.
2000, 267, 6118). NADPH serves as reducing agent of Trx-1 via TrxR
Day Billy W.
Lazo John S.
Wipf Peter
Covington Raymond
Rotman Alan L.
The University of Pittsburgh
Thorp Reed & Armstrong LLP
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