Cancer wars: natural products strike back

Natural products have historically been a mainstay source of anticancer drugs, but in the 90's they fell out of favor in pharmaceutical companies with the emergence of targeted therapies, which rely on antibodies or small synthetic molecules identified by high throughput screening. Although targeted therapies greatly improved the treatment of a few cancers, the benefit has remained disappointing for many solid tumors, which revitalized the interest in natural products. With the approval of rapamycin in 2007, 12 novel natural product derivatives have been brought to market. The present review describes the discovery and development of these new anticancer drugs and highlights the peculiarities of natural product and new trends in this exciting field of drug discovery.

[1]  Andreas Kirschning,et al.  Merging chemical synthesis and biosynthesis: a new chapter in the total synthesis of natural products and natural product libraries. , 2012, Angewandte Chemie.

[2]  Daniel,et al.  There are no bad anticancer agents, only bad clinical trial designs--twenty-first Richard and Hinda Rosenthal Foundation Award Lecture. , 1998 .

[3]  R. Noble,et al.  Short communicationsFurther biological activities of vincaleukoblastine—an alkaloid isolated from Vinca rosea (L.) , 1959 .

[4]  B. Kahan,et al.  Preclinical evaluation of a new potent immunosuppressive agent, rapamycin. , 1991, Transplantation.

[5]  N. Ribeiro,et al.  Prohibitin Ligands in Cell Death and Survival: Mode of Action and Therapeutic Potential , 2013, Chemistry & Biology.

[6]  L. Mevellec,et al.  The first semi-synthesis of enantiopure homoharringtonine via anhydrohomoharringtonine from a preformed chiral acyl moiety☆☆☆ , 1999 .

[7]  Benjamin N. Roin Unpatentable Drugs and the Standards of Patentability , 2009 .

[8]  G. Kerley,et al.  The Alkaloids of Cephalotaxus drupacea and Cephalotaxus fortunei , 1963 .

[9]  J. Heitman,et al.  Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast , 1991, Science.

[10]  A. Limberg,et al.  Total Synthesis of (−)‐Epothilone A , 1997 .

[11]  O. Legrand,et al.  Semisynthetic homoharringtonine induces apoptosis via inhibition of protein synthesis and triggers rapid myeloid cell leukemia-1 down-regulation in myeloid leukemia cells , 2006, Molecular Cancer Therapeutics.

[12]  Sreejith Shankar,et al.  The generation of "unnatural" products: synthetic biology meets synthetic chemistry. , 2012, Natural product reports.

[13]  B. Hill,et al.  Markedly diminished drug resistance-inducing properties of vinflunine (20′,20′-difluoro-3′,4′-dihydrovinorelbine) relative to vinorelbine, identified in murine and human tumour cells in vivo and in vitro , 2001, Cancer Chemotherapy and Pharmacology.

[14]  Nicholas H Oberlies,et al.  Romidepsin (Istodax, NSC 630176, FR901228, FK228, depsipeptide): a natural product recently approved for cutaneous T-cell lymphoma , 2011, The Journal of Antibiotics.

[15]  C. Milstein,et al.  Continuous cultures of fused cells secreting antibody of predefined specificity , 1975, Nature.

[16]  Thomas Henkel,et al.  Statistical Investigation into the Structural Complementarity of Natural Products and Synthetic Compounds. , 1999, Angewandte Chemie.

[17]  F. Lee,et al.  BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  M. Campone,et al.  Vinflunine: a novel antitubulin agent in solid malignancies , 2005, Expert opinion on investigational drugs.

[19]  Thomas Henkel,et al.  Statistical Investigation into the Structural Complementarity of Natural Products and Synthetic Compounds. , 1999, Angewandte Chemie.

[20]  B. Zhu,et al.  Total synthesis of epothilone A. , 2000, Organic letters.

[21]  M. Yoshida,et al.  FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. , 1998, Experimental cell research.

[22]  R. Huber,et al.  Crystal structure of the 20 S proteasome:TMC-95A complex: a non-covalent proteasome inhibitor. , 2001, Journal of molecular biology.

[23]  Natividad Rodríguez,et al.  Synthesis of natural ecteinascidins (ET-729, ET-745, ET-759B, ET-736, ET-637, ET-594) from cyanosafracin B. , 2003, The Journal of organic chemistry.

[24]  C. Gerhardt Untersuchungen über die wasserfreien organischen Säuren , 1853 .

[25]  D. Weisleder,et al.  Antitumor Alkaloids from Cephalotaxus harringtonia: Structure and Activity , 1972 .

[26]  S. Danishefsky,et al.  Stereospecific formal total synthesis of ecteinascidin 743. , 2006, Angewandte Chemie.

[27]  C. Bailly Ready for a comeback of natural products in oncology. , 2009, Biochemical pharmacology.

[28]  E. Raymond,et al.  Mechanism of action of rapalogues: the antiangiogenic hypothesis. , 2008, Expert opinion on investigational drugs.

[29]  C. Fairchild,et al.  Eleutherobin, a New Cytotoxin that Mimics Paclitaxel (Taxol) by Stabilizing Microtubules , 1997 .

[30]  P. Baran,et al.  14-Step Synthesis of (+)-Ingenol from (+)-3-Carene. , 2014 .

[31]  G. Mathé,et al.  Effet sur la leucémie 1210 de la souris d'un combinaison par diazotation d'A-méthoptèrine et de gamma-globulines de hamsters porteurs de cette leucèmie par hétérogreffe. , 1958 .

[32]  A. Phillips,et al.  The halichondrins and E7389. , 2009, Chemical reviews.

[33]  D. V. Von Hoff There are no bad anticancer agents, only bad clinical trial designs--twenty-first Richard and Hinda Rosenthal Foundation Award Lecture. , 1998, Clinical Cancer Research.

[34]  G. Cordell,et al.  Natural products and traditional medicine: turning on a paradigm. , 2012, Journal of natural products.

[35]  Y. Nishizuka The role of protein kinase C in cell surface signal transduction and tumour promotion , 1984, Nature.

[36]  D. Weedon,et al.  Home treatment of basal cell carcinoma. , 1976, The Medical journal of Australia.

[37]  R. Mantovani,et al.  Effect of ecteinascidin-743 on the interaction between DNA binding proteins and DNA. , 1999, Anti-cancer drug design.

[38]  M. Huang,et al.  Harringtonine, an inhibitor of initiation of protein biosynthesis. , 1975, Molecular pharmacology.

[39]  E. Carreira,et al.  Stereoselective syntheses of epothilones A and B via directed nitrile oxide cycloaddition. , 2001, Journal of the American Chemical Society.

[40]  R. Huber,et al.  Crystal Structure of Epoxomicin:20S Proteasome reveals a molecular basis for selectivity of alpha,beta-Epoxyketone Proteasome Inhibitors , 2000 .

[41]  J. Chien,et al.  Trends in translational medicine and drug targeting and delivery: new insights on an old concept-targeted drug delivery with antibody-drug conjugates for cancers. , 2014, Journal of pharmaceutical sciences.

[42]  R. Calne,et al.  The development of immunosuppression: the rapamycin milestone. , 2003, Transplantation proceedings.

[43]  R. Breinbauer,et al.  Activity-based protein profiling for natural product target discovery. , 2012, Topics in current chemistry.

[44]  E. Corey,et al.  Enantioselective Total Synthesis of Ecteinascidin 743 , 1996 .

[45]  A. Kirschning,et al.  Highly Active Ansamitocin Derivatives: Mutasynthesis Using an AHBA‐Blocked Mutant , 2008, Chembiochem : a European journal of chemical biology.

[46]  C. Mercurio,et al.  Towards Selective Inhibition of Histone Deacetylase Isoforms: What Has Been Achieved, Where We Are and What Will Be Next , 2014, ChemMedChem.

[47]  L. Ducry Challenges in the development and manufacturing of antibody-drug conjugates. , 2012, Methods in molecular biology.

[48]  B. Hill,et al.  Vinflunine (20′,20′-difluoro- 3′,4′-dihydrovinorelbine), a novel Vinca alkaloid, which participates in P-glycoprotein (Pgp)-mediated multidrug resistance in vivo and in vitro , 2004, Investigational New Drugs.

[49]  S. Ogbourne,et al.  PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: Results of a randomized, double‐blind, vehicle‐controlled, multicentre, phase IIa study , 2009, The Australasian journal of dermatology.

[50]  K. Nicolaou,et al.  Total Syntheses of Epothilones A and B via a Macrolactonization-Based Strategy. , 1997 .

[51]  Tae-You Kim,et al.  Phase I and Pharmacokinetic Study of Genexol-PM, a Cremophor-Free, Polymeric Micelle-Formulated Paclitaxel, in Patients with Advanced Malignancies , 2004, Clinical Cancer Research.

[52]  Andrés Francesch,et al.  Development of Yondelis (trabectedin, ET-743). A semisynthetic process solves the supply problem. , 2009, Natural product reports.

[53]  R. Mantovani,et al.  Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Zhiguo Xu Modernization: One step at a time , 2011, Nature.

[55]  P. Clemons,et al.  Distinct Biological Network Properties between the Targets of Natural Products and Disease Genes , 2010, Journal of the American Chemical Society.

[56]  S. Mooberry,et al.  Laulimalide and isolaulimalide, new paclitaxel-like microtubule-stabilizing agents. , 1999, Cancer research.

[57]  S. Sehgal,et al.  Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. , 1975, The Journal of antibiotics.

[58]  Robert M. Williams,et al.  Synthetic studies on Et-743. Assembly of the pentacyclic core and a formal total synthesis. , 2008, The Journal of organic chemistry.

[59]  Shyam Sundar,et al.  Injectable paromomycin for Visceral leishmaniasis in India. , 2007, The New England journal of medicine.

[60]  J. Rosenberg,et al.  Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer , 2012, Drug design, development and therapy.

[61]  M. Okuhara,et al.  FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. , 1987, The Journal of antibiotics.

[62]  B. E. Evans,et al.  Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists. , 1988, Journal of Medicinal Chemistry.

[63]  H Irschik,et al.  Epothilons A and B: antifungal and cytotoxic compounds from Sorangium cellulosum (Myxobacteria). Production, physico-chemical and biological properties. , 1996, The Journal of antibiotics.

[64]  Pankaj Chopra,et al.  Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model. , 2005, Journal of medicinal chemistry.

[65]  M. Rowlands,et al.  Novel Steroidal Inhibitors of Human Cytochrome P45017α (17α -Hydroxylase-C17,20-lyase): Potential Agents for the Treatment of Prostatic Cancer. , 1995 .

[66]  The X-ray crystal structure of rapamycin, C51H79NO13 , 1978 .

[67]  E. Raymond,et al.  Phase I and pharmacokinetic study of the new vinca alkaloid vinflunine administered as a 10-min infusion every 3 weeks in patients with advanced solid tumours. , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[68]  P. Baran,et al.  14-Step Synthesis of (+)-Ingenol from (+)-3-Carene , 2013, Science.

[69]  E. Raymond,et al.  Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells , 2008, British Journal of Cancer.

[70]  M. Okuhara,et al.  FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. , 1987, The Journal of antibiotics.

[71]  C. Lalueza-Fox,et al.  Neanderthal medics? Evidence for food, cooking, and medicinal plants entrapped in dental calculus , 2012, Naturwissenschaften.

[72]  P. K. Ajikumar,et al.  The future of metabolic engineering and synthetic biology: towards a systematic practice. , 2012, Metabolic engineering.

[73]  T. Ghose,et al.  Suppression of an AKR lymphoma by antibody and chlorambucil. , 1975, Journal of the National Cancer Institute.

[74]  Susan Band Horwitz,et al.  Total Synthesis of (–)‐Epothilone B: An Extension of the Suzuki Coupling Method and Insights into Structure–Activity Relationships of the Epothilones , 1997 .

[75]  M. D’Incalci,et al.  Preclinical and clinical results with the natural marine product ET-743 , 2003, Expert opinion on investigational drugs.

[76]  Y. Pommier,et al.  Poisoning of human DNA topoisomerase I by ecteinascidin 743, an anticancer drug that selectively alkylates DNA in the minor groove. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[77]  S. Sehgal,et al.  Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization.:II. FERMENTATION, ISOLATION AND CHARACTERIZATION , 1975 .

[78]  Christopher P Leamon,et al.  Engineering folate-drug conjugates to target cancer: from chemistry to clinic. , 2012, Bioconjugate chemistry.

[79]  C. Fairchild,et al.  Eleutherobin, a New Cytotoxin that Mimics Paclitaxel (Taxol) by Stabilizing Microtubules. , 1997 .

[80]  J. Ribet,et al.  Vinca Alkaloids in Superacidic Media: A Method for Creating a New Family of Antitumor Derivatives , 1997 .

[81]  M. Jarman,et al.  The 16,17-double bond is needed for irreversible inhibition of human cytochrome p45017alpha by abiraterone (17-(3-pyridyl)androsta-5, 16-dien-3beta-ol) and related steroidal inhibitors. , 1998, Journal of medicinal chemistry.

[82]  M. Jordan,et al.  Microtubules as a target for anticancer drugs , 2004, Nature Reviews Cancer.

[83]  Paul A. Keifer,et al.  Ecteinascidins 729, 743, 745, 759A, 759B, and 770: potent antitumor agents from the Caribbean tunicate Ecteinascidia turbinata , 1990 .

[84]  S. Kuduk,et al.  A common pharmacophore for cytotoxic natural products that stabilize microtubules. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[85]  S. Thiru,et al.  RAPAMYCIN FOR IMMUNOSUPPRESSION IN ORGAN ALLOGRAFTING , 1989, The Lancet.

[86]  I. G. Collado,et al.  Chemical genetics strategies for identification of molecular targets , 2013, Phytochemistry Reviews.

[87]  Cephalotaxine esters in the treatment of acute leukemia. A preliminary clinical assessment. , 1976, Chinese medical journal.

[88]  A. Ganesan The impact of natural products upon modern drug discovery. , 2008, Current opinion in chemical biology.

[89]  Y. Hasegawa,et al.  EGFR-TKI resistance due to BIM polymorphism can be circumvented in combination with HDAC inhibition. , 2013, Cancer research.

[90]  P. Low,et al.  Delivery of macromolecules into living cells: a method that exploits folate receptor endocytosis. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[91]  Craig J. Forsyth,et al.  Total synthesis of halichondrin B and norhalichondrin B , 1992 .

[92]  M. Ochiai,et al.  X-Ray crystal structure of rocaglamide, a novel antileulemic 1H-cyclopenta[b]benzofuran from Aglaia elliptifolia , 1982 .

[93]  Jieping Zhu,et al.  Synthetic studies toward ecteinascidin 743. , 2005, The Journal of organic chemistry.

[94]  D. Swinney,et al.  How were new medicines discovered? , 2011, Nature Reviews Drug Discovery.

[95]  I. Bièche,et al.  Epithelial-to-mesenchymal transition and resistance to ingenol 3-angelate, a novel protein kinase C modulator, in colon cancer cells. , 2009, Cancer research.

[96]  Shutao Ma,et al.  The Medicinal Potential of Promising Marine Macrolides with Anticancer Activity , 2011, ChemMedChem.

[97]  Mathieu Pucheault,et al.  Natural products: chemical instruments to apprehend biological symphony. , 2008, Organic & biomolecular chemistry.

[98]  Ulrich Beyer,et al.  Liposomal encapsulated anti-cancer drugs. , 2005, Anti-cancer drugs.

[99]  S. Schreiber,et al.  Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[100]  D. Bearss,et al.  The inefficiency of incisions of ecteinascidin 743-DNA adducts by the UvrABC nuclease and the unique structural feature of the DNA adducts can be used to explain the repair-dependent toxicities of this antitumor agent. , 2001, Chemistry & biology.

[101]  H. Rosing,et al.  Phase I and pharmacokinetic study of ecteinascidin-743, a new marine compound, administered as a 24-hour continuous infusion in patients with solid tumors. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[102]  N. Ribeiro,et al.  Flavaglines: potent anticancer drugs that target prohibitins and the helicase eIF4A. , 2013, Future medicinal chemistry.

[103]  D. Weisleder,et al.  Structures of harringtonine, isoharringtonine, and homoharringtonine. , 1970, Tetrahedron letters.

[104]  K. Nicolaou,et al.  Total Synthesis of Epothilone A: The Olefin Metathesis Approach , 1997 .

[105]  Gisbert Schneider,et al.  Scaffold diversity of natural products: inspiration for combinatorial library design. , 2008, Natural product reports.

[106]  S. Horwitz Taxol (paclitaxel): mechanisms of action. , 1994, Annals of oncology : official journal of the European Society for Medical Oncology.

[107]  M. Avery,et al.  Total syntheses of epothilones B and d. , 2004, The Journal of organic chemistry.

[108]  Stuart L. Schreiber,et al.  A mammalian protein targeted by G1-arresting rapamycin–receptor complex , 1994, Nature.

[109]  C. Galmarini,et al.  A Review of Trabectedin (ET-743): A Unique Mechanism of Action , 2010, Molecular Cancer Therapeutics.

[110]  C. Milstein,et al.  Continuous cultures of fused cells secreting antibody of predefined specificity. 1975. , 1992, Biotechnology.

[111]  S. Sehgal,et al.  Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. , 1975, The Journal of antibiotics.

[112]  Robert Langer,et al.  Nanoparticle delivery of cancer drugs. , 2012, Annual review of medicine.

[113]  G. Schulte,et al.  Discodermolide: a new bioactive polyhydroxylated lactone from the marine sponge Discodermia dissoluta , 1990 .

[114]  J. Tanaka,et al.  Norhalichondrin A: an antitumor polyether macrolide from a marine sponge , 1985 .

[115]  M. M. El-Missiry,et al.  Constituents of Egyptian Euphorbiaceae. IX. Irritant and cytotoxic ingenane esters fromEuphorbia paralias L. , 1980, Experientia.

[116]  S. Kuduk,et al.  Structural requirements of taxoids for nitric oxide and tumor necrosis factor production by murine macrophages. , 1996, Biochemical and biophysical research communications.

[117]  Aravind Subramanian,et al.  Tight Coordination of Protein Translation and HSF1 Activation Supports the Anabolic Malignant State , 2013, Science.

[118]  M. Fresno,et al.  Inhibition of translation in eukaryotic systems by harringtonine. , 1977, European journal of biochemistry.

[119]  M. Okuhara,et al.  FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity. , 1994, The Journal of antibiotics.

[120]  M. Rowlands,et al.  Novel steroidal inhibitors of human cytochrome P45017 alpha (17 alpha-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer. , 1995, Journal of medicinal chemistry.

[121]  G. Alexander,et al.  Sirolimus: a potent new immunosuppressant for liver transplantation. , 1999, Transplantation.

[122]  A. Kruczynski,et al.  Bcl-2 down-regulation and tubulin subtype composition are involved in resistance of ovarian cancer cells to vinflunine , 2006, Molecular Cancer Therapeutics.

[123]  G. Schneider,et al.  Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product-based combinatorial libraries. , 2001, Journal of combinatorial chemistry.

[124]  Y. Nishizuka,et al.  [The role of protein kinase C in cell surface signal transduction and tumor promotion]. , 1986, Gan to kagaku ryoho. Cancer & chemotherapy.

[125]  E. Raymond,et al.  Phase I and pharmacokinetic study of the new vinca alkaloid vinflunine administered as a 10min infusion every 3 weeks in patients with advanced solid tumours , 2002 .

[126]  G. Mathé,et al.  [Effect on mouse leukemia 1210 of a combination by diazo-reaction of amethopterin and gamma-globulins from hamsters inoculated with such leukemia by heterografts]. , 1958, Comptes rendus hebdomadaires des seances de l'Academie des sciences.

[127]  S. Jin,et al.  Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[128]  M. Jarman,et al.  The 16,17-Double Bond Is Needed for Irreversible Inhibition of Human Cytochrome P45017α by Abiraterone (17-(3-Pyridyl)androsta-5,16-dien-3β-ol) and Related Steroidal Inhibitors. , 1999 .

[129]  Paroma Basu Trading on traditional medicines , 2004, Nature Biotechnology.

[130]  H. Reichenbach,et al.  Epothilone A and B—Novel 16-Membered Macrolides with Cytotoxic Activity: Isolation, Crystal Structure, and Conformation in Solution† , 1996 .

[131]  E. Lazarides,et al.  Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. , 1995, Cancer research.

[132]  A. Balog,et al.  Totalsynthese von (—)‐Epothilon A , 1996 .

[133]  Minoru Yoshida,et al.  FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. , 2002, Cancer research.

[134]  B. Cvek Nonprofit drugs as the salvation of the world's healthcare systems: the case of Antabuse (disulfiram). , 2012, Drug discovery today.

[135]  J. Findlay,et al.  On the chemistry and high field nuclear magnetic resonance spectroscopy of rapamycin , 1980 .

[136]  A. Green,et al.  HOME TREATMENT OF SKIN CANCER AND SOLAR KERATOSES , 1988, The Australasian journal of dermatology.

[137]  Y. Pommier,et al.  Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair , 2001, Nature Medicine.

[138]  G. Campiani,et al.  Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77. , 2009, Cancer research.

[139]  J. Mulzer,et al.  Total syntheses of epothilones B and D. , 2000, The Journal of organic chemistry.

[140]  A Ganesan,et al.  Natural products and combinatorial chemistry: back to the future. , 2004, Current opinion in chemical biology.

[141]  T. Vasaitis,et al.  Novel, potent anti-androgens of therapeutic potential: recent advances and promising developments. , 2010, Future medicinal chemistry.

[142]  F. Lee,et al.  Preclinical discovery of ixabepilone, a highly active antineoplastic agent , 2008, Cancer Chemotherapy and Pharmacology.

[143]  L. Nguyen,et al.  Phase I study of Vinflunine administered as a 10-minute infusion on days 1 and 8 every 3 weeks , 2006, Investigational New Drugs.

[144]  H. Komatsu [Antibody therapy in cancer]. , 2010, Nihon rinsho. Japanese journal of clinical medicine.

[145]  Zhuang Liu,et al.  Drug delivery with carbon nanotubes for in vivo cancer treatment , 2008, 0808.2070.

[146]  J. McAlpine,et al.  Revised NMR assignments for rapamycin. , 1991, The Journal of antibiotics.

[147]  A. Balog,et al.  Total Synthesis of Epothilone A. , 1996 .

[148]  F. de la Calle,et al.  Synthesis of ecteinascidin ET-743 and phthalascidin Pt-650 from cyanosafracin B. , 2000, Organic letters.

[149]  T. Kan,et al.  Total synthesis of ecteinascidin 743. , 2002, Journal of the American Chemical Society.

[150]  Philip S Low,et al.  Evaluation of disulfide reduction during receptor-mediated endocytosis by using FRET imaging , 2006, Proceedings of the National Academy of Sciences.

[151]  Susan O'Brien,et al.  Homoharringtonine/omacetaxine mepesuccinate: the long and winding road to food and drug administration approval. , 2013, Clinical lymphoma, myeloma & leukemia.

[152]  K. Kohn,et al.  DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata. , 1996, Biochemistry.

[153]  T. Fukuyama,et al.  Synthetic Studies toward Ecteinascidin 743 (Trabectedin) , 2012 .

[154]  L. Hurley,et al.  Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major groove. , 1999, Journal of medicinal chemistry.

[155]  D. Uemura,et al.  Halichondrins - antitumor polyether macrolides from a marine sponge , 1986 .

[156]  J. Lord,et al.  Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells , 2008, Molecular Cancer Therapeutics.

[157]  P. Vrignaud,et al.  Preclinical Antitumor Activity of Cabazitaxel, a Semisynthetic Taxane Active in Taxane-Resistant Tumors , 2013, Clinical Cancer Research.

[158]  M. Hidalgo,et al.  A phase I and pharmacokinetic study of ecteinascidin-743 on a daily x 5 schedule in patients with solid malignancies. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[159]  M. Okuhara,et al.  Action of FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum no. 968, on Ha-ras transformed NIH3T3 cells. , 1994, Bioscience, biotechnology, and biochemistry.