Methods for preparation and use of psorospermin analogs
AssigneesBoard of Regents, The University of Texas System, Cylene Pharmaceuticals, Inc.
InventorsLaurence Hurley, Ingrid Fellows, Michael Kenric Schwaebe, Jeffrey Paul Whitten
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Abstract
Psorospermin is a cytotoxic dihydroflranoxanthone that has found to exhibit significant activity against various tumor cell lines. Unfortunately, psorospermin is no longer readily available from its natural plant source. The present invention is directed to a method for preparing psorospermin and psorospermin analogs. Methods are also disclosed for utilizing psorospermin analogs to inhibit cellular proliferation.
Claims31
A process of preparing a compound of the formula:
- 90
- wherein each R1-R4 and R6 is independently H, OH, O-alkyl, halogen, or alkyl;
- R5 is H, O-alkyl, or alkyl;
- R7 is CH2;
- and
- R8 is H or alkyl;
- the process comprising:
- reacting compound of the formula:
- 91
- wherein R1-R6 and R8 are as defined above, and R7 is CH3;
- with Pd((CH3CN)4(BF4)2) or Pd(OCOCF3)2 and benzoquinone in DMSO.
A process for preparing (−) psorospermin analogs having a formula:
- 95
- wherein each of R1-R4 and R6 is independently H, OH, O-alkyl, OCH3, halogen, or alkyl;
- R5 is H, O-alkyl, or alkyl;
- and
- R8 is H or alkyl;
- the process comprising performing chiral separation chromatography on an unresolved mixture of stereoisomers of a compound of the formula:
- 96
- wherein R1-R8 are as above-defined.
A process for preparing a psorospermin analog having a formula:
- 97
- wherein each of R1-R4 and R6 is independently H, OH, O-alkyl, halogen, or alkyl;
- R5 is H, O-alkyl, or alkyl;
- and
- R8 is H or alkyl;
- the process comprising:
- 98
- treating a compound of the formula:
- wherein R1-R4 and R8are defined above and R7′is CH2;
- with a dihydroxylating agent and a chiral ligand to obtain a dihydroxylated product, followed by epoxidation of the dihydroxylated product.
A method for identifying patients with a BMI-1 related cancer, the method comprising:
- a) obtaining a first sample from a patient;
- b) measuring the amount of BMI-1 protein or nucleic acid in the first sample;
- c) comparing the amount of BMI-1 protein or nucleic acid in the first sample with a second sample obtained from a non-cancerous subject;
- wherein an increased amount of BMI-1 protein or nucleic acid in the first sample relative to the second sample indicates a BMI-1 related cancer.
A pharmaceutical composition comprising a compound of the formula:
- 104
- each of R1-R4 and R6 is independently H, OH, O-alkyl, halogen, or alkyl;
- R5 is H, O-alkyl, or alkyl;
- and
- R8 is H or alkyl.
A method of treating a subject with a hyperproliferative disorder comprising administering to the subject a compound of the formula:
- 105
- each of R1-R4 and R6 is independently H, OH, O-alkyl, halogen, or alkyl;
- R5 is H, O-alkyl, or alkyl;
- and
- R8 is H or alkyl.
A compound of the formula:
- 106
- wherein each of R1-R4 and R6 is H, OH, O-alkyl, halogen, or alkyl;
- R5 is H, O-alkyl, or alkyl;
- R7 is CH3;
- and
- R8 is H or alkyl.
A compound of the formula:
- 107
- wherein each of R1-R4 and R6 is independently H, OH, O-alkyl, halogen, or alkyl;
- R5 is H, O-alkyl, or alkyl;
- R7 is CH2;
- and
- R8 is H or alkyl.
A compound of the formula:
- 108
- wherein each of R1-R4 and R6 is independently H, OH, O-alkyl, halogen, or alkyl;
- R5 is H,O-alkyl;
- and
- R8is H or alkyl.
A compound of the formula:
- 109
- wherein each of R1-R4 and R6 is independently H, OH, O-alkyl, halogen, or alkyl;
- R5 is H, O-alkyl, or alkyl;
- and
- R8 is H or alkyl.
Dependencies are inferred from the claim text.