Covalent conjugates between endoperoxides and transferrin and lactoferrin receptor-binding agents

Abstract

The invention relates to covalent conjugates between endoperoxides and small peptides and organic compounds that bind to molecular cavities on the transferrin or lactoferrin receptor, and the use of compositions comprising these conjugates to treat cancer, hyperproliferative disorders, inflammatory diseases, and infections.

1 . A compound comprising at least one endoperoxide containing moiety covalently linked to a receptor binding agent that binds to a transferrin receptor or a lactoferrin receptor on a cell without interfering with transferrin or lactoferrin binding to the same receptor. 
     
     
         2 . The compound of  claim 1 , wherein the endoperoxide containing moiety comprises an endoperoxide bridge. 
     
     
         3 . The compound of  claim 2 , wherein the endoperoxide bridge is a 1,2,4-trioxane bridge or a 1,2,4,5-tetraoxane bridge. 
     
     
         4 . The compound of  claim 3 , wherein the endoperoxide containing moiety is an artemisinin-related endoperoxide. 
     
     
         5 . The compound of  claim 1 , wherein the receptor binding agent is a peptide. 
     
     
         6 . The compound of  claim 5 , wherein the peptide is selected from the group consisting of SEQ ID NO: 1 and SEQ ID NO: 2. 
     
     
         7 . A composition comprising a compound comprising at least one endoperoxide containing moiety covalently linked to a receptor binding agent that binds to a transferrin receptor or a lactoferrin receptor on a cell without interfering with transferrin or lactoferrin binding to the receptor, and a pharmaceutically acceptable carrier. 
     
     
         8 . A method of treating a human or animal subject for a disease or condition selected from the group consisting of cancer; restenosis; proliferative eye, kidney, and skin diseases; precancerous hyperplastic conditions, benign prostatic hyperplasia (BPH), benign breast disease (BBD); autoimmune disease; arthritis; graft rejection; inflammatory bowl disease; proliferation induced after medical procedures; an infection by a pathogenic organism that has a receptor for transferrin or lactoferrin; topical bacterial infections; gingivitis; skin infections; eye infections; and malaria; comprising administering to said subject a therapeutically effective amount of a composition comprising a compound comprising at least one endoperoxide containing moiety covalently linked to a receptor binding agent that binds to a transferrin receptor or a lactoferrin receptor on a cell without interfering with transferrin or lactoferrin binding to the same receptor. 
     
     
         9 . The method of  claim 8 , wherein the endoperoxide containing moiety comprises an endoperoxide bridge. 
     
     
         10 . The method of  claim 9 , wherein the endoperoxide bridge is a 1,2,4-trioxane bridge or a 1,2,4,5-tetraoxane bridge. 
     
     
         11 . The method of  claim 10 , wherein the endoperoxide containing moiety is an artemisinin-related endoperoxide. 
     
     
         12 . The method of  claim 8 , wherein receptor binding agent is a peptide. 
     
     
         13 . The method of  claim 8 , wherein the subject is human. 
     
     
         14 . The method of  claim 8 , wherein the disease or condition is selected from the group consisting of cancer, precancerous hyperplastic conditions, BPH, and BPD. 
     
     
         15 . The method of  claim 8 , comprising administering an effective amount of the covalent conjugate in combination with an agent that increases iron transport into cells. 
     
     
         16 . The method of  claim 15 , wherein the agent that increases iron transport into cells is selected from the group consisting of insulin, insulin-like growth factor I, epidermal growth factor, erythropoietin, interleukin-4, interleukin-10, interleukin-13, and dexrazoxane.