Anti-cancer compounds and methods for treating cancer

Abstract

The present invention is directed to novel anti-cancer compounds and methods of treating and/or inhibiting cancer in patients, including metastatic cancer, recurrent cancer and drug resistant cancers, including multiple drug resistant cancers. Compounds according to the present invention provide anti-cancer activity, at least in part, by virtue of their nucleotide intercalating activity through the use of analogs of (−)lomaiviticin A, a potent anticancer agent which exhibits cytotoxicity through its principal mechanism of cleavage and to a lesser extent, its intercalation of cellular polynucleotides, especially DNA. In additional embodiments, compounds according to the present invention are also conjugated and/or linked to other bioactive agents, especially agents which selectively target cancer cells (cancer cell targeting moiety or CCTM) to target and increase the delivery of the anticancer agent to the cancer cell. These targeting agents include folate receptor-targeted moieties, other cancer binding moieties such as PMSA binding moieties as otherwise described herein and antibodies, including single chain variable fragment antibodies (scFv antibodies). Pharmaceutical compositions based upon these novel compounds are also disclosed pursuant to the present invention. Methods of treating, inhibiting and/or reducing the likelihood of cancer, including metastatic and recurrent cancer and drug resistant, including multiple drug resistant cancer in a patient are also disclosed.

1 . A compound for use as an anti-cancer agent comprising at least one intercalating moiety (ILM) which is capable of intercalating and/or cleaving DNA of cytotoxic cells in a patient to be treated for cancer and at least one cancer cell targeting moiety (CCTM) wherein said at least one CCTM group is covalently linked to said ILM group through an optional linker. 
     
     
         2 . The compound according to  claim 1  wherein said linker is cleavable or non-cleavable linker. 
     
     
         3 . A compound according to the chemical structure: 
       
         
           
           
               
               
           
         
         where Y is a bond or CH—R S  group; 
         R 4  and R 5  are each independently OH, C 1 -C 3  alkyl, O—(C 1 -C 3 )alkyl, a OC(O)—(C 1 -C 3 ) alkyl group, a C(O)O—C 1 -C 3 ) or L-CCTM (preferably both R 4  and R 5  are OH); 
         R 6  and R 7  are each independently H, C 1 -C 3  alkyl, OH, O—(C 1 -C 3 )alkyl, halo (F, Cl, Br or I), a OC(O)—(C 1 -C 3 ) alkyl group, a C(O)O—C 1 -C 3 ) or L-CCTM; 
         R A  and R B  are each independently H, C 1 -C 3  alkyl (preferably, ethyl or H and ethyl) or L-CCTM; 
         R D  is H, C 1 -C 3  alkyl, O(C 1 -C 3 ) alkyl, an optionally substituted aryl group or forms a dimer compound with the compound to which R D  is attached (in certain preferred embodiments, R D  is H or the compound to which R D  is attached and R D  form a dimer) 
         R S  is H, a 
       
       
         
           
           
               
               
           
         
       
       group where n is 0, 1, 2, 3, 4, or 5 and one or more of the methylene groups when present are optionally substituted with OH, OCH 3  or CH 3 , or R S  is a sugar moiety containing a 4-amino group which is optionally substituted with a L-CCTM group or one or two C 1 -C 3  alkyl groups which alkyl groups may be optionally substituted with one or two alcohol groups, preferably R S  is a sugar moiety according to the chemical structure: 
       
         
           
           
               
               
           
         
         where X is O, S, N—R N  or CH 2  (preferably O); 
         R N  is H or a C 1 -C 3  alkyl group (preferably H); 
         R 1  and R 2  are each independently H, a C 1 -C 3  alkyl group optionally substituted with one or two alcohol groups (preferably methyl) or a L-CCTM group; 
         R 1 , R 2  and R 3  are each independently H, OH, a halo group (F, Cl, Br, I), O—(C 1 -C 3 )alkyl, a C 1 -C 3  alkyl, a C 2 -C 4  acyl group, a OC(O)—(C 1 -C 3 ) alkyl group, a C(O)O—C 1 -C 3 ) alkyl group or a L-CCTM group; 
         L is a bond or a linker group; and 
         CCTM is a cancer cell targeting moiety which binds to a cancer cell, 
         or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. 
       
     
     
         4 . A compound according to the chemical structure: 
       
         
           
           
               
               
           
         
         where R 1  and R 2  are each independently H, a C 1 -C 3  alkyl group (preferably methyl) or a L-CCTM group; 
         R 1 , R 2  and R 3  are each independently H, OH, O—(C 1 -C 3 )alkyl, a C 1 -C 3  alkyl or a L-CCTM group; 
         R 4  and R 5  are each independently OH, C 1 -C 3  alkyl, O—(C 1 -C 3 )alkyl or L-CCTM (preferably both are OH); 
         R 6  and R 7  are each independently H, C 1 -C 3  alkyl, OH, O—(C 1 -C 3 )alkyl, halo (F, Cl, Br or I) or L-CCTM; 
         R A  and R B  are each independently H, C 1 -C 3  alkyl (preferably, ethyl or H and ethyl) or L-CCTM; 
         R D  is H or forms a dimeric compound with the compound to which RD is attached (preferably R D  and the compound to which R D  is attached are identical and attached at the same position); 
         L is absent (a bond) or a linker group (preferably, a cleavable linker group); and 
         CCTM is a cancer cell targeting moiety which binds to a cancer cell, 
         or a pharmaceutically acceptable salt, stereoisiomer, solvate or polymorph thereof. 
       
     
     
         5 . A compound according to the chemical structure: 
       
         
           
           
               
               
           
         
         Where R 1  and R 2  are each independently H, CH 3  or L-CCTM (preferably, both are CH 3 ); 
         R 1  is H, C 1 -C 3  alkyl or L-CCTM, (preferably CH 3 ); 
         R 2  is H, OH or L-CCTM, (preferably OH) ;    
         R 3  is H, CH 3 , or L-CCTM, (preferably H); 
         R 6  and R 7  are each independently H or L-CCTM; 
         R A  and R B  are each independently H, ethyl, or L-CCTM; and 
         R D  is H or forms a dimeric compound with the compound to which RD is attached (preferably R D  and the compound to which R D  is attached are identical and attached at the same position); 
         L is absent (a bond) or a linker group, which may be a cleavable linker group or a non-cleavable linker group depending on the CCTM group; and 
         CCTM is a cancer cell targeting moiety which binds to a cancer cell, 
         or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. 
       
     
     
         6 . A compound according to the chemical structure: 
       
         
           
           
               
               
           
         
         where each R C  is independently OH or a L-CCTM group; 
         L is absent (a bond) or a linker group, which may be a cleavable linker group or a non-cleavable linker group; and 
         CCTM is a cancer cell targeting moiety which binds to a cancer cell, 
         or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. 
       
     
     
         7 . A compound according to the chemical structure: 
       
         
           
           
               
               
           
         
         where R C  is OH or a L-CCTM group; 
         L is absent (a bond) or a linker group, which may be a cleavable linker group or a non-cleavable linker group; and 
         CCTM is a cancer cell targeting moiety which binds to a cancer cell, 
         or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. 
       
     
     
         8 . A compound according to the chemical structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         where R C  is OH or a L-CCTM group; 
         L is absent (a bond) or a linker group, which may be a cleavable linker group or a non-cleavable linker group; and 
         CCTM is a cancer cell targeting moiety which binds to a cancer cell, 
         or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. 
       
     
     
         9 . A compound according to the chemical structure: 
       
         
           
           
               
               
           
         
         where R is H or CH 3  with the proviso that at least one R is CH 3  (preferably, all R are CH 3 ); and 
         Linker is a linker group which is optionally substituted with a CCTM group. 
       
     
     
         10 . A compound according to the chemical structure: 
       
         
           
           
               
               
           
         
         where R L  is H or a L-CCTM group; 
         L is absent (a bond) or a linker group, which may be a cleavable linker group or a non-cleavable linker group; and 
         CCTM is a cancer cell targeting moiety which binds to a cancer cell, 
         or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. 
       
     
     
         11 . The compound according to  claim 1  wherein said CCTM group is a folate receptor binding moiety, a monoclonal antibody, an antibody fragment (FAB), a single chain variable fragment (scFv) antibody, a PSMA binding moiety or a YSA peptide. 
     
     
         12 . The compound according to  claim 11  wherein said folate receptor binding moiety is a moiety according to the chemical structure: 
       
         
           
           
               
               
           
         
         where X F  is C(O), S(O), S(O) 2 , CR F R F , O, S or N—R F ; and 
         R F  is H or a C 1 -C 3  alkyl (preferably H). 
       
     
     
         13 . The compound according to  claim 1  wherein said CCTM group is a YSA peptide having the sequence YSAYPDSVPMMS (SEQ ID NO: 1). 
     
     
         14 . The compound according to  claim 3  wherein said CCTM group is a PSMA group according to the chemical structure: 
       
         
           
           
               
               
           
         
         Where X 1  and X 2  are each independently CH 2 , O, NH or S; 
         X 3  is O, CH 2 , NR 1 , S(O), S(O) 2 , —S(O) 2 O, —OS(O) 2 , or OS(O) 2 O; 
         R 1  is H, a C 1 -C 3  alkyl group, or a —C(O)(C 1 -C 3 ) group; and 
         k is an integer from 0 to 20; 
         or a salt or enantiomer thereof. 
       
     
     
         15 . The compound according to  claim 14  wherein said PSMA binding group is the group 
       
         
           
           
               
               
           
         
         or a salt or enantiomer thereof. 
       
     
     
         16 . The compound according to  claim 1  wherein said CCTM group is herceptin. 
     
     
         17 . The compound according to  claim 1  wherein said linker group is a cleavable linker. 
     
     
         18 . The compound according to  claim 1  wherein said linker group is a non-cleavable linker. 
     
     
         19 . The compound according to  claim 17  wherein said linker comprises a group according to the chemical structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         where R is an ethylene glycol group, a methylene group or an amino acid, preferably an ethylene glycol group or an amino acid and n is from 0 to 10, often from 1 to 6, or 1 to 3 and where points of attachment (as indicated) are to other portions of the cleavable linker, a difunctional connector moiety (CON), a non-cleavable (non-labile) linker (L N ), or a multifunctional connector molecule [MULTICON], through which an [ILM] functional group and a [CCTM] functional group are linked as otherwise described herein; 
         X is O, N—R AL  or S; 
         R AL  is H or a C 1 -C 3  alkyl group (often H or Me, most often H); 
         Y is O or S and 
         Z=Me, Et, iPr, tBu, phenyl, each of which may be optionally substituted with one or more halogen groups (especially from three up to five Fs, preferably no more than three Fs) and wherein said phenyl group may be further optionally substituted with a C 1 -C 3  alkyl group (which itself may be substituted with up to three halogens, preferably F) or OMe. 
       
     
     
         20 . The compound according to  claim 17  wherein said linker comprises a group according to the chemical structure: 
       
         
           
           
               
               
           
         
         Where R is independently an ethylene glycol group, a methylene group or an amino acid where at least one amino acid (that which provides one of the sulfurs in the disulfide group) is a cysteinyl group and n in this labile linker is from 0 to 10. 
       
     
     
         21 . The compound according to  claim 17  wherein said linker comprises a group according to the chemical structure: 
       
         
           
           
               
               
           
         
         Where the protease substrate is a a peptide containing from 2 to 50 amino acid units; 
         R is an ethylene glycol group or a methylene group and n is from 0 to 10. 
       
     
     
         22 . The compound according to  claim 21  wherein said protease substrate consists essentially of the peptide
 -Gly-Phe-Leu-Gly-; 
 -Ala-Leu-Ala-Leu; 
 -Phe-Arg-; 
 -Phe-Lys-; 
 -Val-Cit- (valine-citrillune) 
 -Val-Lys-; or 
 -Val-Ala-. 
 
     
     
         23 . The compound according to  claim 17  wherein said cleavable linker is a beta-glucosidase linker consisting essentially of moiety according to the chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound according to  claim 18  wherein said linker is a (poly)ethylene glycol linker ranging in length from 2 to about 100 ethylene glycol units or a polyethylene-co-polypropylene (PEG/PPG block copolymer) linker ranging from 2 to about 100 ethylene glycol and propylene glycol units. 
     
     
         25 . The compound according to  claim 18  wherein said linker is according to the chemical formula: 
       
         
           
           
               
               
           
         
         where R a  is H or a C 1 -C 3  alkyl; 
         m is an integer from 1 to 12; 
         m″ is an integer 1, 2, 3, 4, 5, or 6; 
         t is 0, 1, 2, 3, 4, 5, or 6; and 
         iL is 0 or 1. 
       
     
     
         26 . The compound according to  claim 1  wherein said linker is according to the chemical structure: 
       
         
           
           
               
               
           
         
         Where q is an integer from 0-12; 
         q′ is 1 to 12 and 
         iL is 0 or 1. 
       
     
     
         27 . The compound according to  claim 1  wherein said linker is according to the chemical structure: 
       
         
           
           
               
               
           
         
         Where q is an integer from 0-12, preferably 0, 1, 2, 3, 4, 5 or 6; 
         q′ is 1 to 12, often 1, 2, 3, 4, 5 or 6; 
         iL is 0 or 1; and 
         R L  is an amino acid or an oligopeptide. 
       
     
     
         28 . The compound according to  claim 3  where R S  is a 
       
         
           
           
               
               
           
         
       
       group where n is 0, 1, 2, 3, 4, or 5 and one or more of the methylene groups when present are optionally substituted with OH or CH 3 , or R S  is a sugar moiety containing a 4-amino group which is optionally substituted with a L-CCTM group or one or two C 1 -C 3  alkyl groups which alkyl groups may be optionally substituted with one or two alcohol groups. 
     
     
         29 . The compound according to  claim 3  wherein R S  is a group according to the chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         30 . A pharmaceutical composition comprising an effective amount of a compound according to  claim 1  in combination with a pharmaceutically acceptable carrier, additive and excipient and optionally in further combination with another anticancer agent. 
     
     
         31 . The composition according to  claim 30  wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or a mixture thereof. 
     
     
         32 . The composition according to  claim 30  wherein said additional anticancer agent is everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase inhibitors, an AKT inhibitor, a JAKISTAT inhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab (Arzerra), zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001 IPdR 1  KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperadinemethyl)-indolylj-quinolone, vatalanib, AG-013736, AVE-0005, the acetate salt of [D-Ser(Bu t) 6, Azgly 10] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH 2  acetate [C 59 H 84 N 18 Oi 4 -(C 2 H 4 O 2 ) X  where x=1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafamib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD 121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody) and erbitux, cremophor-free paclitaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa or a mixture thereof. 
     
     
         33 . A method of treating cancer comprising administering to a patient in need an effective amount of a composition according to  claim 30  to said patient. 
     
     
         34 . The method according to  claim 33  wherein said cancer is a naïve, metastatic, drug resistant, DNA repair response deficient (DDR-deficient), hypoxic or multiple drug resistant cancer. 
     
     
         35 . The method according to  claim 33  wherein said cancer is tumorous. 
     
     
         36 . The method according to  claim 33  wherein said cancer is DNA repair response deficient (DDR-deficient) or hypoxic. 
     
     
         37 . The method according to  claim 36  wherein said cancer is DDR-deficient. 
     
     
         38 . The method according to  claim 37  wherein said cancer is deficient in KU80, BRCA2, pten, DNApk, ATM, PALB2 and/or RAD51 paralogs. 
     
     
         39 . The method according to  claim 36  wherein said cancer is hypoxic. 
     
     
         40 . The method according to  claim 33  wherein said cancer is carcinomas (e.g., squamous-cell carcinomas, adenocarcinomas, hepatocellular carcinomas, and renal cell carcinomas), particularly those of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, particularly Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, and synovial sarcoma; tumors of the central nervous system (e.g., gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas); germ-line tumors (e.g., bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine/endometrial cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, and melanoma); mixed types of neoplasias, particularly carcinosarcoma and Hodgkin's disease; and tumors of mixed origin, such as Wilms' tumor and teratocarcinomas. 
     
     
         41 . The method according to  claim 37  wherein said cancer is ovarian, breast, colon, pancreatic prostate, melanoma, head, neck or brain cancer (glioma). 
     
     
         42 . The method according to  claim 33  wherein said compound is combined with an additional anticancer agent. 
     
     
         43 . The method according to  claim 33  wherein said treatment is combined with radiation therapy. 
     
     
         44 . A method of inhibiting metastasis of cancer in a patient in need comprising administering to said patient a compound according to  claim 1 , optionally in combination with at least one additional anticancer agent. 
     
     
         45 . The method according to  claim 44  wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or a mixture thereof. 
     
     
         46 . The method according to  claim 44  wherein said additional anticancer agent is everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101 pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase inhibitors, an AKT inhibitor, a JAK/STAT inhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubiein, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab (Arzerra), zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR 1  KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperadinemethyl)-indolylj-quinolone, vatalanib, AG-013736, AVE-0005, the acetate salt of [D-Ser(Bu t) 6, Azgly 10] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH 2  acetate [C 59 H 84 N 18 Oi 4 -(C 2 H 4 O 2 ) X  where x=1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafamib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody) and erbitux, cremophor-free paclitaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa or a mixture thereof. 
     
     
         47 . A method of treating cancer comprising administering to a patient in need an effective amount of (−)-lomaiviticin A (LA), MK7-206 or a mixture thereof. 
     
     
         48 . The method according to  claim 47  wherein said cancer is a naïve, metastatic, drug resistant, DNA repair response deficient (DDR-deficient), hypoxic or multiple drug resistant cancer. 
     
     
         49 . The method according to  claim 47  wherein said cancer is tumorous. 
     
     
         50 . The method according to  claim 47  wherein said cancer is DNA repair response deficient (DDR-deficient) or hypoxic. 
     
     
         51 . The method according to  claim 50  wherein said cancer is DDR-deficient. 
     
     
         52 . The method according to  claim 51  wherein said cancer is deficient in non-homologous enjoining and/or homologous recombination repair mechanism. 
     
     
         53 . The method according to  claim 51  wherein said cancer is deficient in KU80, BRCA2, pten, DNApk, ATM, PALB2 and/or RAD51 paralogs repair factors. 
     
     
         54 . The method according to  claim 50  wherein said cancer is hypoxic. 
     
     
         55 . The method according to  claim 47  wherein said cancer is carcinomas (e.g., squamous-cell carcinomas, adenocarcinomas, hepatocellular carcinomas, and renal cell carcinomas), particularly those of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, particularly Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, and synovial sarcoma; tumors of the central nervous system (e.g., gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas); germ-line tumors (e.g., bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine/endometrial cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, and melanoma); mixed types of neoplasias, particularly carcinosarcoma and Hodgkin's disease; and tumors of mixed origin, such as Wilms' tumor and teratocarcinomas. 
     
     
         56 . The method according to  claim 50  wherein said cancer is ovarian, breast, pancreatic, colon, prostate, melanoma, head, neck or brain cancer (glioma). 
     
     
         57 . The method according to  claim 47  wherein said compound is combined with an additional anticancer agent. 
     
     
         58 . The method according to  claim 47  wherein said treatment is combined with radiation therapy.