The Scripps Research Institute

Other

Trustees of the Univ. of Penna.

K C Nicolaou

Philippe G Nantermet

Rodney K Guy

Hiroaki Ueno

Claus G Riemer

Michael A Kerr

Erik J Sorensen

Wolfgang Wrasidlo

Emmanuel Pitsinos

Elias A Couladouros

Christopher F Claiborne

Jin-Jun Liu

Wolfgang J Wrasidlo

Andrew C Hiatt

Chan-Kou Hwang

Zhen Yang

Golfo Skokotas

Emmanuel N Pitsinos

Erik J Sorenson

Peter Maligres

Guido Zaccarello

Onium salts of taxo-diterpenoid-C,,2-O-aza-arenes form water soluble self-assembling nanostructures above a critical aggregation concentration. The onium salt of aza-arene includes a delocalized charge which renders derivatized taxo-diterpenoids amphoteric, enhances their solubility in water, and promotes self-assembly of water soluble nanostructures, e.g., helical fibular structures and spherical micellular structures. These same onium salts of taxo-diterpenoid-C,,2-O-aza-arenes are employed as water soluble prodrugs. For example, taxol-2&prime;-methylpyridinium tosylate (MPT) is characterized by an elevated aqueous solubility, rapid activation by serum protein, good stability in most other aqueous solutions, formation of a protein:taxol intermediate and good retention within the circulatory system. The toxicity of the activated form is comparable or greater than underivatized taxol. Furthermore, taxol-2&prime;-MPT can be synthesized by a simple one step reaction between taxol and 2-fluoro-1-MPT. The invention is applicable to taxol and taxol memetics having hydroxyls that are reactive with onium salts of 2-halogenated-aza-arenes. For example, taxol, C-2 substituted taxol and Taxotere each have reactive hydroxyls at the 2&prime; and 7 positions. The invention is also applicable to a wide array of 2-halogenated-aza-arenes.

Self-assembled taxo-diterpenoid nanostructures

Cyclic chemical switching method is employed for solubilizing and desolubilizing taxo-diterpenoids with respect to aqueous solvents. 2-Halogenated onium salts of aza-arenes are employed to derivatize taxo-diterpenoids so as to alter their solubility in aqueous solvents. The onium salt of aza-arene includes a delocalized charge which imparts polarity and aqueous solubility to taxo-diterpenoid derivatives. Solubilization is achieved in a one step derivatization with the onium salt of 2-halogenated aza-arenes. Desolubilization is achieved by contacting onium salts of taxo-diterpenoid-C,,2-O-aza-arenes with serum protein to displace the 2-O-aza-arene and form a soluble protein:taxo-diterpenoid intermediate. This protein:taxo-diterpenoid intermediate then dissociates over time to provide a bioactive taxo-diterpenoid. These same onium salts of taxo-diterpenoid-C,,2-O-aza-arenes are employed as water soluble prodrugs. The toxicity of the activated form is comparable or greater than underivatized taxol. The invention is applicable to taxol and taxol memetics having hydroxyls that are reactive with onium salts of 2-halogenated-aza-arenes.

Chemical switching of taxo-diterpenoids between low solubility active forms and high solubility inactive forms

Alkaline sensitive protaxol is water soluble and is hydrolyzed at physiological (alkaline) pH to render the native taxol structure and the native taxol activity. Protaxol compositions include 2'- and/or 7-O-ester derivatives of taxol and/or 2'- and/or 7-O-carbonate derivatives taxol. Protaxol has a formula as follows: ##STR1## wherein R.sup.1 and R.sup.2 are each H or a radical selected from the group consisting of --CO--(CH.sub.2).sub.m --X--(CH.sub.2).sub.n --COZ and --COO--(CH.sub.2).sub.o --Y--Ar, and wherein m, n, and o are each an integer of 1 to 3; X is 0, S, NH, SO, or SO.sub.2 ; Y is S, SO or SO.sub.2 ; Ar is phenyl or substituted phenyl wherein the substituent is halo, amino, nitro or N,N-dialkylamino having 1 to 4 carbons in each of the alkyl groups; and Z is OH, OR.sup.3, SR.sup.3 or NR.sup.4 R.sup.5 wherein R.sup.3 is alkyl containing 1 to 4 carbons and R.sup.4 and R.sup.5 are each alkyl containing 1 to 4 carbons, or taken together with the nitrogen to which they are attached form a saturated heterocyclic ring having 4 or 5 carbons, with the proviso that at least on R.sup.1 and R.sup.2 is not hydrogen; as well as the salts of such compounds with organic/inorganic bases and acids, preferably pharmaceutically acceptable salts.

Water soluble taxol derivatives

Bioactive ABC taxoids accessible by convergent synthesis have an intact AB ring framework of taxol, including the C.sup.13 side chain, and an aromatic C ring which substitutes for the CD ring system found on native taxol. The aromatic C ring may be substituted or unsubstituted. MPT derivatives of ABC taxoids are also disclosed.

Taxoid synthesis

Transformations of taxol, baccatin III and of 10-deacetyl baccatin III provide access to novel taxol analogs and key intermediates thereto.

Access to taxol analogs

Alkaline sensitive protaxol is water soluble and is hydrolyzed at physiological (alkaline) pH to render the native taxol structure and the native taxol activity. Protaxol compositions include 2'- and/or 7-O-ester derivatives of taxol and/or 2'- and/or 7-O-carbonate derivatives taxol. Protaxol has a formula as follows: ##STR1## wherein R.sup.1 and R.sup.2 are each H or a radical selected from the group consisting of --CO--(CH.sub.2).sub.m --X--(CH.sub.2).sub.n --COZ and --COO--(CH.sub.2).sub.o --Y--Ar, and wherein m, n, and o are each an integer of 1 to 3; X is O, S, NH, SO, or SO.sub.2 ; Y is S, SO or SO.sub.2 ; Ar is phenyl or substituted phenyl wherein the substituent is halo, amino, nitro or N,N-dialkylamino having 1 to 4 carbons in each of the alkyl groups; and Z is OH, OR.sup.3, SR.sup.3 or NR.sup.4 R.sup.5 wherein R.sup.3 is alkyl containing 1 to 4 carbons and R.sup.4 and R.sup.5 are each alkyl containing 1 to 4 carbons, or taken together with the nitrogen to which they are attached form a saturated heterocyclic ring having 4 or 5 carbons, with the proviso that at least one R.sup.1 and R.sup.2 is not hydrogen; as well as the salts of such compounds with organic/inorganic bases and acids, preferably pharmaceutically acceptable salts.

Synthetic calicheamicin mimics employ alternative activation triggers and trigger cites and include tithers for conjugation to DNA targeting systems.

Calicheamicin mimics

A method for esterifying C13 deoxy taxoid intermediates employs three steps, i.e., oxygenation of the C13 deoxy taxoid intermediate to produce a C13 enone taxoid intermediate; reduction of the C13 enone to produce an alcohol; followed by esterification of the C13 alcohol. Key intermediates include C13 deoxy taxoids; C13 enone substituted taxoids; and C1-C2 cyclo carbonate esters of taxoids.

Transformations of taxol

A method for inducing apoptosis in target cells employs designed enediynes which are triggered to become chemically reactive when bound to target cells. Conversely, a method for inhibiting the induction of apoptosis employs compounds which compete with the above compounds which induce apoptosis, but which are chemically unreactive with respect to the target cells.

Induction and inhibition of apoptosis

The total synthesis of taxol employs a convergent synthetic plan. The synthetic plan may also be employed to produce a large number of taxol analogs. Taxol analogs having skeletal extensions are inaccessible by modification of the natural product but are readily produced by employing the convergent synthetic plan herein.

Total synthesis of taxol and taxol analogs

Alkaline sensitive protaxol is water soluble and is hydrolyzed at physiological (alkaline) pH to render the native taxol structure and the native taxol activity. Protaxol compositions include 2'- and/or 7-O-ester derivatives of taxol and/or 2'- and/or 7-O-carbonate derivatives taxol. Protaxol has a formula as follows: ##STR1## wherein R.sup.1 and R.sup.2 are each H or a radical selected from the group consisting of --CO--(CH.sub.2).sub.m --X--(CH.sub.2).sub.n --COZ and --COO--(CH.sub.2).sub.o --Y--Ar, and wherein m, n, and o are each an integer of 1 to 3; X is O, S, NH, SO, or SO.sub.2 ; Y is S, SO or SO.sub.2 ; Ar is phenyl or substituted phenyl wherein the substituent is halo, amino, nitro or N,N-dialkylamino having 1 to 4 carbons in each of the alkyl groups; and Z is OH, OR.sup.3, SR.sup.3 or NR.sup.4 R.sup.5 wherein R.sup.3 is alkyl containing 1 to 4 carbons and R.sup.4 and R.sup.5 are each alkyl containing 1 to 4 carbons, or taken together with the nitrogen to which they are attached form a saturated heterocyclic ring having 4 or 5 carbons, with the proviso that at least on R.sup.1 and R.sup.2 is not hydrogen; as well as the salts of such compounds with organic/inorganic bases and acids, preferably pharmaceutically acceptable salts.

A taxol intermediate selected from the group consisting of: ##STR1## wherein R.sup.1 and R.sup.2 are the same or different and each selected from hydrogen, hydroxyl, or a protected hydroxyl; or R.sup.1 and R.sup.2 together form an oxo or a protected oxo; R.sup.3 is formyl, a protected formyl, or --CH(X)--OY wherein X is hydrogen or a monovalent metal and Y is hydrogen or a hydroxyl protecting group; and R.sup.4 and R.sup.5 are different and each selected from chloro or cyano; or R.sup.4 and R.sup.5 together form an oxo or a protected oxo, with the proviso that R.sup.1 and R.sup.2 are not both hydroxyl; R.sup.6 is hydroxyl or a protected hydroxyl; R.sup.7 is hydrogen, hydroxyl, or a protected hydroxyl; R.sup.8 is carboxyl, hydroxylmethyl, or a protected hydroxylmethyl; or R.sup.7 and R.sup.8 when taken together with carbon atoms 3 and 4, form an oxetane ring; or R.sup.6 and R.sup.8 when taken together with carbon atoms 1 and 4, form a bridged lactone; R.sup.9 is hydrogen or a hydroxyl protecting group; R.sup. 10 is hydroxyl or a protected hydroxyl; or R.sup.8 and R.sup.10 when taken together with carbon atoms 4 and 5, form a .gamma.-butyrolactone ring; R.sup.11 is alkoxycarbonyl, formyl, a protected formyl, hydroxylmethyl or a protected hydroxylmethyl; or R.sup.6 and R.sup.11 when taken together with carbon atoms 1 and 6, form a 2,2-dimethyl-1,3-dioxane ring; and the dotted line between the 2- and 3-positions of the six-membered ring represents an optional bond.

Intermediates for preparation of taxols

Propargylic and allenic sulfones are disclosed having the ability to selectively cleave nucleic acids, especially deoxyribonucleic acid. Such compositions are capable of being synthetically modified to effect cleavage at selected, sequenced sites on nucleic acids.

Growing community of inventors

La Jolla, CA, United States of America

K C Nicolaou