Dihydroartemisinin derivatives and methods of making and use thereof
OwnerChi-Ming CHE, Yiu Chung Gulice LEUNG +1inventors
InventorsChi-Ming CHE, Yiu Chung Gulice LEUNG, Mei-Ling RUAN
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Abstract
Dihydroartemisinin (“DHA”) derivatives that contain a stereospecific C-10 ether linkage and an aryl pharmacophore moiety are disclosed. In some forms, the DHA derivatives possess anticancer properties that are comparable to or better than the parent DHA and/or an existing anticancer drug (e.g., Cisplatin), and are useful in anticancer treatments (such as ovarian cancer and colon cancer). Methods of synthesizing the DHA derivatives that are cost effective are disclosed. Methods of using the DHA derivatives for treating a cancer, such as ovarian cancer and/or colon cancer, in a subject in need thereof are also disclosed.
Claims20
A compound having the structure of:
- wherein:
- (i) R1 is an electron withdrawing group;
- (ii) n1 is an integer from 0 to 5, from 1 to 5, from 1 to 4, from 1 to 3, or 1 or 2, such as 1;
- and
- (iii) L′ is
- (a) n2 is an integer from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, or 1 or 2;
- (b) A′ is a bond,
- each occurrence of Y and Z are independently O or S, optionally A′ is a bond,
- and
- (c) R2 and R3 are independently hydrogen or an alkyl (such as an unsubstituted C1-C6 alkyl, a substituted C1-C6 alkyl, an unsubstituted C1-C5 alkyl, a substituted C1-C5 alkyl, an unsubstituted C1-C4 alkyl, a substituted C1-C4 alkyl, an unsubstituted C1-C3 alkyl, a substituted C1-C3 alkyl, for example, a methyl, an ethyl, an n-propyl, an isopropyl, an n-butyl, an iso-butyl, a tert-butyl, an n-pentyl, an iso-pentyl, a tert-pentyl, an n-hexyl, an iso-hexyl, or a tert-hexyl, each optionally substituted with a hydroxyl, a thiol, an alkoxy, a carboxylic acid, a ketone, an aldehyde, or an ester).
A method for synthesizing DHA derivatives having a structure of Formula IVa, Formula IVb, or Formula IVc:
- wherein:
- (i) X1 is a halide (e.g., bromide), hydroxyl, or thiol;
- (ii) n3 is an integer from 0 to 5, from 1 to 5, from 1 to 4, from 1 to 3, or 1 or 2, such as 1;
- (iii) L1 is a bond,
- each occurrence of Y and Z are independently O or S (such as
- R3 is hydrogen or an alkyl (such as an unsubstituted C1-C6 alkyl, an unsubstituted C1-C5 alkyl, an unsubstituted C1-C4 alkyl, an unsubstituted C1-C3 alkyl, a methyl, or an ethyl);
- and (iv) R7 is an alkyl (e.g., methyl or ethyl) or
- the method comprising:
- (a) maintaining a first reaction mixture at a temperature of 0° C. to room temperature for a time period of 2 hours to 15 hours, from 5 hours to 15 hours, or from 5 hours to 10 hours to form a first product comprising the DHA derivatives of Formula IVa and Formula IVb,
- wherein the first reaction mixture comprises DHA, a first reactant having the structure of Formula V, a catalyst, and an organic solvent,
- wherein:
- X1 and n3 are as defined for Formula IVa and Formula IVb;
- and T1 is hydroxyl,
- R3 is as defined above for Formula IVa, IVb, and IVc.
A method for synthesizing a DHA derivative having the structure of Formula IIa or Formula IIb,
- wherein:
- (i) R1 is an electron withdrawing group;
- (ii) n1 is an integer from 0 to 5, from 1 to 5, from 1 to 4, from 1 to 3, or 1 or 2, such as 1;
- (iii) n2 is an integer from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, or 1 or 2;
- and (iv) A′ is a bond,
- each occurrence of Y and Z are independently O or S, optionally A′ is a bond,
- wherein R2 and R3 are independently hydrogen or an alkyl (such as an unsubstituted C1-C6 alkyl, a substituted C1-C6 alkyl, an unsubstituted C1-C5 alkyl, a substituted C1-C5 alkyl, an unsubstituted C1-C4 alkyl, a substituted C1-C4 alkyl, an unsubstituted C1-C3 alkyl, a substituted C1-C3 alkyl, for example, a methyl, an ethyl, an n-propyl, an isopropyl, an n-butyl, an iso-butyl, a tert-butyl, an n-pentyl, an iso-pentyl, a tert-pentyl, an n-hexyl, an iso-hexyl, or a tert-hexyl, each optionally substituted with a hydroxyl, a thiol, an alkoxy, a carboxylic acid, a ketone, an aldehyde, or an ester),
- the method comprising:
- (b) maintaining a second reaction mixture at a temperature of −10° C. to room temperature for a time period of 2 hours to 15 hours, from 5 hours to 15 hours, or from 5 hours to 10 hours to form an intermediate product comprising an intermediate of Formula VI or Formula VIII;
- and (c) converting the intermediate of Formula VI or Formula VIII to a second product comprising the DHA derivative of Formula IIa or Formula IIb,
- wherein the second reaction mixture comprises DHA, a second reactant having the structure of Formula VII, a catalyst, and an organic solvent,
- wherein n2 is an integer from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, or 1 or 2;
- and X1 is a halide or hydroxyl.
Dependencies are inferred from the claim text.