Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-12-11
2001-01-09
Lee, Howard C. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C514S025000, C514S032000, C536S017300, C536S018100, C548S300100, C548S311100, C548S311400
Reexamination Certificate
active
06172205
ABSTRACT:
BACKGROUND OF THE INVENTION
Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
The marine environment is taking its place beside plant sources and fermentation in providing access to biologically active substances (30). From the standpoint of organic chemistry, this aquatic biomass warrants particularly close attention, due to the richly varied structures provided therein. Moreover, the reliability of marine feedstocks as a bulk source of natural products is often less than the case with their plant and microbially derived counter parts. Hence, marine derived natural products may well furnish excellent opportunities for the subspecialty of synthesis.
Such an opportunity is presented by a group of structurally related natural products which is loosely group under the term “eleuthesides” (cf. inter alia eleutherobin (31), sarcodictyn (32) and valdivone (33).
These are each isolated from different marine sources. Interest in the family was considerably heightened by the recent report that eleutherobin displays excellent potency in a variety of tumor cell lines and that the mechanism of its cytotoxicity promotes the polymerization of stable microtubules (31). Thus, at least eleutherobin, manifests a taxol-epothilone-discodermolide mode of action (34). In light of the very interesting structures of these closely related compounds, the high potency of eleutherobin, and the difficult availablity of all of the eleuthesides from their natural habitats, this family presents a challenging opportunity for creative chemistry.
Eleutherobin, a natural product isolated from a marine soft coral, is an antimitotic agent that promotes the polymerization of stable microtubules. Although its mechanism of action is similar to that of Taxol, its structure is distinct. A structure-activity profile of five synthetic eleutherobin derivatives that have modifications at C3, C8 and C15 is reported. Cytotoxicity, the ability to polymerize stable microtubules and the induction of microtubule bundles in cells were assessed. Eleutherobin had an IC
50
value comparable at Taxol, whereas neo-eleutherobin, which carries a carbohydrate domain that is enantiomeric with that of the parental product, had 690 of the microtubule polymerization ability of eleutherobin and was 20-fold less cytotoxic. Both of these compounds exhibited cross-resistance in an MDR1 expressing cell line, Removal or replacement of the C15 sugar moiety resulted in reduced microtubule polymerization and cytotoxicity compared to eleutherobin and loss of cross-resistance at the ovarian carcinoma cell line SKVBL that expresses high levels of P-glycoprotein. Hence, removal of the sugar moiety alters the cytotoxic potency of eleutherobin and its cross-resistance pattern in Taxol-resistant cells, though such compounds retain the microtubule stabilizing activity of eleutherobin. By contrast, removal of the urocanic acid group at C8 resulted in virtually complete abrogation of biological activity. The compound lost is ability to polymerize microtubules, and its cytotoxicity was reduced by a minimum of 2000-fold in lung carcinoma A549 cells. Thus, our data indicate that the N(1)-methylurocanic acid moiety of eleutherobin or a structurally similar moiety is essential for Taxol-like activity. These findings will be important for the future design and synthesis of new and. more potent eleutherobin analogues.
Synthesis of the tricyclic core of eleutherobin and sarcodictyn has been reported by Nicolaou. (46) Additional work by Nicolaou includes a total synthesis of eleutherobin from the tricyclic core. (47, 48). This invention differs from the work of Nicolaou by providing a different synthetic process toward synthesis of the eleutherobin tricyclic core, eleutherobin and eleutherobin analogues.
The taxol-like activity of eleutherobin and sarcodictyins has been reported on by others. (48, 49) The mechanism of this activity was further investigated by Nicolaou. (50)
This invention provides a flexible and convergent synthesis of the eleuthesides providing significant quantities of end products, going beyond the completion of a ceremonial level route to the natural products.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of a Eleutherobin derivative of the formula:
wherein
R
1
is a hydrogen, ester, nitrile, friflate or CH
2
-R
4
wherein
R
4
is a carbohydrate, an alcohol an amine, an amide, an alkyne,or C
1
-C
9
linear or branched chain alkyl;
R
2
is a linear or branched alkyl moiety;
R
3
is an ester, an amide, a carbamate, an acetal compound, an ether or a urethane;
position C
2
and C is cis or trans;
position C
8
is &agr; or &bgr;, comprising the steps of:
(a) treating a chiral matrix material with a ketene wherein, the chiral matrix material comprises R-(−)-&agr;-phellandrene, under suitable conditions to form a compound having the structure:
wherein X is a halogen; and
(b) Dehalogenating the compound in step (a) under suitable conditions to form a compound having the structure:
(c) subjecting the compound in step (b) to a Bredereck transformation to form a compound having the structure:
(d) acid catalyzing and fragmenting the compound in step(c) under suitable conditions to form a compound having the structure:
(e) appending a furanoid building block having the structure:
wherein M is selected from a group consisting of a metal, and the furanoid building block consists of 2,5-dibromofuran,to the compound formed in step (d) under suitable conditions to form a compound having the structure:
wherein X is &agr;-OH, &bgr;-H or &agr;-H, &bgr;-OH, &agr;-OTBDPS, or &bgr;-OTBDPS
(f) protecting the compound formed in step (e) under suitable conditions to form a compound having the structure:
wherein X is &agr;-OTBDPS, &bgr;-H or &agr;-H, &bgr;-OTBDPS;
(g) expanding the compound in step (f) under suitable conditions to form a compound having the structure:
(h) performing a Nozaki-Kishi reaction on the compound in step (g) to form a compound having the structure:
(i) protecting the compound formed in step (h) under suitable conditions to form a compound having the structure:
(j) treating the compound in step (i) under conditions suitable to the removal of OTBDPS to form a compound having the structure:
(k) treating the compound in step (j) with dimethyldioxirane under suitable conditions to form a compound having the structure:
(l) protecting the compound in step (k) wherein, the protecting group consists of &agr;-OTBDPS, &bgr;-H or &agr;-H, &bgr;-OTBDPS,under suitable conditions to form a compound having the structure:
(m) methylating the compound in step (k) or (l) under suitable conditions to form a compound having the structure:
(n) treating compound (2) in step (m) with acetic anhydride under suitable conditions to form a compound having the structure:
(o) acid catalyzing compound (1) in step (m) under suitable conditions to form a compound having the structure:
wherein
R is a linear or branched chain alkyl group.
(p) protecting, deprotecting and converting the compound in step (o) under suitable conditions to form a compound having the structure:
wherein
R is a linear or branched chain alkyl group and P is a protecting group.
(q) treating the compound in step (p) under suitable conditions to form a compound having the structure:
Wherein the compound in step (q) can be coupled to a carbohydrate, the carbohydrate consiting of D-arabinose, L-arabinose or D-galactose or a compound having the structure:
Wherein
P
2
, P
3
, P
4
, are Ac, H or other alkyl, acetyl groups; P
2
is H, SEM, or TBS when P
3
and P
4
are C(Me)
2
; and the carbohydrate is synthesized by converting a compound:
The present invention provides compound having the structure:
The present invention further provides a compound having the structure:
The present invention also provides a compound having the
Bhattacharya Samit K.
Chen Xiao-Tao
Danishefsky Samuel J.
Gutteridge Clare E.
Zhou Bishan
Cooper & Dunham LLP
Lee Howard C.
The Trustees of Columbia in the City of New York
White John P.
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