Water-soluble Prodrug Research Articles

Isavuconazonium: first global approval.

Isavuconazonium (Cresemba®) is a water-soluble prodrug of the triazole antifungal isavuconazole (BAL 4815), a 14-α-demethylase inhibitor, under development by Basilea Pharmaceutica International Ltd and Astellas Pharma Inc. Isavuconazonium, in both its intravenous and oral formulations, was approved for the treatment of invasive aspergillosis and invasive mucormycosis (formerly termed zygomycosis) in the US in March 2015. Isavuconazonium is under regulatory review in the EU for invasive aspergillosis and mucormycosis. It is also under phase III development worldwide for the treatment of invasive candidiasis and candidaemia. This article summarizes the milestones in the development of isavuconazonium leading to the first approval for invasive aspergillosis and mucormycosis.

Discovery of a potent microtubule-targeting agent: Synthesis and biological evaluation of water-soluble amino acid prodrug of combretastatin A-4 derivatives.

Amino acid prodrugs are known to be very useful for improving the aqueous solubility of sparingly water soluble drugs (Drug Discovery Today 2013, 18, 93). Therefore, we synthesized eleven novel combretastatin A-4 amino acid derivatives and evaluated their anti-tumor activities in vitro and in vivo. Among them, compound 15 (valine attached to compound 3, which was shown to be a potent tubulin polymerization inhibitor in our previous study) exhibited high efficacy in tumor-bearing mice, and pharmacokinetic analysis in rats indicated that compound 15 was an effective prodrug as well. Besides, compound 15 significantly inhibited tubulin polymerization in vitro and in vivo by binding to the colchicine binding site. In addition, compound 15 induced cell cycle arrest in the G2/M phase and triggered apoptosis in a caspase-dependent manner. In conclusion, our study showed that compound 15 could have significant anti-tumor activity as a novel microtubule polymerization disrupting agent with improved aqueous solubility.

Theranostic etoposide phosphate/indium nanoparticles for cancer therapy and imaging.

Etoposide phosphate (EP), a water-soluble anticancer prodrug, is widely used for treatment of many cancers. After administration it is rapidly converted to etoposide, its parent compound, which exhibits anticancer activity. Difficulty in parenteral administration necessitates the development of a suitable nanoparticle delivery system for EP. Here we have used indium both as a carrier to deliver etoposide phosphate to tumor cells and as a SPECT imaging agent through incorporation of (111)In. Etoposide phosphate was successfully encapsulated together with indium in nanoparticles, and exhibited dose dependent cytotoxicity and induction of apoptosis in cultured H460 cancer cells via G2/M cell cycle arrest. In a mouse xenograft lung cancer model, etoposide phosphate/indium nanoparticles induce tumor cell apoptosis, leading to significant enhancement of tumor growth inhibition compared to the free drug.

A facile method for synthesizing water-soluble and superior sustained release anti-HIV prodrug SCs-d4T.

To efficiently deliver stavudine (d4T) for AIDS therapy, chitosan-stavudine conjugate (Cs-d4T) was synthesized. However, its poor water-solubility limited its clinical application. In this study, a sulphonated chitosan-stavudine conjugate (SCs-d4T) was synthesized with a mild SO3·Py complex sulphonation strategy. Chemical characteristics and morphology of Cs-d4T and SCs-d4T were performed by NMR, XRD, FTIR, ICP-AES and SEM. SCs-d4T demonstrated satisfactory solubility (106-bold of Cs-d4T solubility), good anti-HIV activity (6-fold of d4T anti-HIV activity), and well sustained release ability. The major release product O-isopropyl-5'-H-phosphonate of d4T (d4T-P-H) showed higher anti-HIV activity than d4T. For further evaluating the influence of linker and sulphonation strategy on anti-HIV activity, chitosan grafted with d4T by succinyl linker (Cs-sd4T) and SCs-d4T sulphonated by oleum were also prepared. The result showed that the O-isopropyl monophosphate linker of Cs-d4T and SO3·Py complex sulphonation strategy revealed higher anti-HIV activity than succinyl linker of Cs-sd4T and oleum sulphonation strategy, respectively.

Primary Treatment of Invasive Mucormycosis (IM) with Isavuconazole (VITAL Study) or Amphotericin Formulations (FungiScope™): Case Matched Analysis

▪Background: Invasive fungal diseases (IFD) are on the rise due to the increasing numbers of immunosuppressed patients including those undergoing high-dose chemotherapy and hematopoietic stem-cell transplantation. Isavuconazole (ISA) is a novel, broad-spectrum antifungal triazole, available as a water-soluble prodrug in IV and oral formulations. IM is a life-threatening IFD with significant mortality and limited treatment options.Methods: The VITAL study was a Phase III, multicenter, open-label, single arm, trial conducted to evaluate efficacy and safety of ISA treatment in patients with rare IFD, including IM. Eligibility criteria and evaluated outcomes are outlined in clinicaltrials.gov, NCT00634049. Patients received IV or PO ISA 200 mg TID for 2 days followed by 200 mg/day. FungiScope – Global Emerging Fungal Infection Registry maintains a global web-based database on rare IFD, including IM. Entrance criteria are outlined in clinicaltrials.gov, NCT01731353. 21 patients from the VITAL study who received ISA for the primary treatment of proven/probable IM were matched (blinded to mortality status) to up-to 3 proven/probable patients with IM who received a formulation of amphotericin B entered in FungiScope based on 3 dichotomous risk factors: severe disease (i.e. CNS/disseminated), surgical debridement, and hematologic malignancy. All-cause mortality through day 42 was summarized.Results: 33 FungiScope matched controls were identified; 14 VITAL cases were matched to a single control each (n=14), 2 VITAL cases were matched to 2 controls each (n=4), and 5 VITAL cases were matched to 3 controls each (n=15). Demographics, treatments, matching criteria and mortality outcomes are shown in Table 1. The crude mortality rate (33.3%) through day 42 from the VITAL cases was similar to the mortality rate (39.4% crude; 41.3% weighted) from the matched controls of FungiScope.Table 1ParameterIsavuconazole VITAL Cases (n=21)FungiScopeTM Amphotericin B Matched Controls (n=33)Treatment, n (%) Isavuconazole Deoxycholate amphotericin B Liposomal amphotericin B Amphotericin B Lipid Complex21 (100) 0 0 00 7 (21) 22 (67) 4 (12)Case year, range2008–20132005–2013Age, median (range)51 (25–77)57 (22–81)Male, n (%)17 (81)22 (67)Race, n (%) White Black/African American Asian12 (57) 1 (5) 8 (38)31 (94) 0 2 (6)Severe Disease,1 n (%)12 (57)13 (39)Surgical Debridement,2 n (%)9 (43)13 (39)Hematologic Malignancy, n (%)11 (52)18 (55)Crude Mortality, n (%)7 (33.3)13 (39.4)Weighted Mortality3 (%)Not Applicable41.33 – Weights were applied according to the ratio of the number of controls matched to each VITAL case.2 – Surgery performed +/– 7 days of the initiation of isavuconazole or amphotericin.1 – CNS Involvement and/or Disseminated DiseaseConclusions: Isavuconazole was as effective as amphotericin B formulations in the primary treatment of invasive mucormycosis based on this matched case comparison of mortality rates from the VITAL study and FungiScope. DisclosuresVehreschild:MJGTV has served at the speakers’ bureau of Pfizer, Merck, Gilead Sciences and Astellas Pharma, received research funding from 3M and Gilead Sciences and is a consultant to Berlin Chemie.: Consultancy, Research Funding, Speakers Bureau. Vehreschild:Astellas, Gilead, Infectopharm, MSD/Merck, Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Marty:Astellas Pharma US, Merck, WHISCON: Honoraria, Research Funding. Perfect:Astellas, Pfizer, Merck, F26, Scynexis, Viarret: Consultancy, Research Funding. Ostrosky-Zeichner:Astellas: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Rahav:Astellas: Research Funding. Zeiher:Astellas Pharma Global Development: Employment. Lee:Astellas: Employment. Maher:Astellas: Employment. Lovell:Astellas Pharma Inc: Consultancy. Engelhardt:Basilea Pharmaceutica International Ltd: Employment. Cornely:Astellas: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Nelarabine Alone or in Combination in High Risk Childhood / Adolescent and Young Adults (AYA) T- Cell Acute Lymphoblastic Leukemia

▪Introduction: T-cell acute lymphoblastic leukemia (T-ALL) represent 15-20% of childhood/adolescent young adults (AYA) ALL. An intensive chemotherapy is generally needed to obtain the same results than in B-lineage ALL. Day 8 Poor Prednisone Response (PPR) and early resistant disease (refractoriness after induction course or MRD level >10-3 at time point 1 (TP1) and/or TP2) remain particularly challenging as relapses are very difficult to treat especially if they occur early. Nelarabine is a water-soluble prodrug of araG (9-B-arabinofuranosylguanine) which is cytotoxic to T lymphoblasts due to the accumulation of araG nucleotides, especially araGTP, which result in inhibition of ribonucleotide reductase and inhibition of DNA synthesis. Nelarabine was shown to be effective and safe in phase II-III adult and pediatric ALL trials. We describe here a 7 consecutive years experience of nelarabine in “real life” in 3 pediatric / AYA centers.Methods: All children and AYA who received nelarabine in first line therapy or after relapse between 2006 and 2013 were reviewed retrospectively. Classical initial prognostic factors were collected: age, leucocytosis, CNS status, day 8 prednisone response, complete remission (CR) or not, minimum residual disease (MRD) level at TP1 and TP2. Eighty two % of the patients (pts) followed the French FRALLE 2000-T recommendations. Nelarabine, alone or in combination, was used in two groups of pts: group 1: pts in whom nelarabine is given in first line therapy because of high MRD level >10-3 at TP1 and/or TP2 (whatever the level at time of nelarabine infusion) and pts refractory to induction course, and group 2: pts in relapse. Group 1 and 2 are compared for MRD level after nelarabine, number of patients able to go to allogeneic HSCT and overall survival. Finally the safety profile was assessed.Results: 33 T-ALL patients received nelarabine alone (n= 22) or in combination (n= 11, most often with cyclophosphamide and etoposide) from 2006 to 2013. At initial diagnosis, median age was 11.6 y old [3-24], sex ratio 4.5 (M/F 27/6) and median leukocytosis 184.7.109/L [0.1-914]. These patients shared poor risk factors: CNS3 (n=8, 24.1%), D8 PPR (n=23, 69.7%), day 21 M3 bone marrow (n=13, 36.4%), no CR after one induction course (n=6, 18.2%) and MRD level > 10-3 at CR1 (n=15, 42.4%). Regarding group 1 (high MRD level at TP1 and/or TP2 n= 11, refractoriness to induction course n= 5), the status just before nelarabine was: 6 in CR1 with finally MRD <10-3, 5 in CR1 but MRD >10-3 and 5 refractory. Nelarabine was given alone in 12 patients and in combination in 4 patients. MRD level after nelarabine was <10-3 in 12/16 patients. Overall, 11 pts received an allogeneic HSCT and 13/16 (81%) are alive in CR1 at the time of the analysis with a median FU from first nelarabine infusion of 13.7 months [0.8-58.3]. Overall survival is 79.8%+/-10.5 at 5 years. Regarding group 2 (relapsed patients, n= 17), nelarabine was infused at the time of first relapse in 4 patients and in refractory first relapse or more than first relapse in 13 patients. Among these heavily pretreated patients, only 6 obtained a MRD level <10-3 leading to allogeneic HSCT but none of 6 survived. Only one patient survived in CR3 after a success of nelarabine alone and received other chemotherapy without allogeneic HSCT. Regarding toxicities, the only WHO grade III-IV observed side effects are cytopenias (n= 25, 75.8%). Others reported side effects are limited (grade I-II): fever of undetermined origin or infections (n= 7, 21.2%), neurological (n= 6 pts, 18.2%; some of them with more than one side effect: sensory neuropathy in 4, motor neuropathy in 2, headaches in 2, motor-facial neuropathy in 1, ataxia in 1) or muscular (n= 4, 12.1%; 2 myalgia, 1 myositis, 1 amyotrophia), liver toxicities (n= 4, 12.1%; 3 transaminase increases, 1 hyperbilirubinemia).Conclusions: In a non selected population of childhood / AYA high-risk T-ALL, nelarabine was very useful for poor risk patients in first line therapy. The majority of patients received nelarabine as a monotherapy. By contrast nelarabine mostly failed to improve the survival in heavily pretreated relapsed patients. Overall, this study conforts the use of nelarabine in first line T-ALL and high-risk features with acceptable tolerance. The evaluation of nelarabine in selected high-risk patients in a first line setting should be evaluated prospectively to confirm these results. DisclosuresBaruchel:JAZZ: Membership on an entity’s Board of Directors or advisory committees; ARIAD: Membership on an entity’s Board of Directors or advisory committees; Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees.

An Improved Design of Water-Soluble Propofol Prodrugs Characterized by Rapid Onset of Action

Lang, Bing-Chen*†; Yang, Jun†; Wang, Yu†; Luo, Yun†‡; Kang, Yi†; Liu, Jin†; Zhang, Wen-Sheng† Author Information

Initial testing (stage 1) of BAL101553, a novel tubulin binding agent, by the pediatric preclinical testing program.

BAL101553 is a highly water soluble prodrug of BAL27862 that arrests tumor cell proliferation and induces cell death in cancer cells through disruption of the microtubule network. In vitro BAL27862 demonstrated potent activity, with the median relative IC50 (rIC50 ) of 13.8 nM (range 5.4-25.2 nM). The in vitro activity of BAL27862 against the PPTP cell lines is distinctive from that previously described for vincristine. BAL101553 induced significant differences in EFS distribution compared to control in 16 of 30 (53%) solid tumor xenografts and in two of four (67%) of the evaluable ALL xenografts. No objective responses were observed.

Water-soluble prodrugs of paclitaxel containing self-immolative disulfide linkers

A new series of disulfide-containing prodrugs of paclitaxel were designed, synthesized and evaluated against 6 cancer cell lines. Some of these prodrugs exhibited nearly equal or slightly better anticancer activity when compared to that of paclitaxel. These prodrugs contain water-soluble groups such as amino, carboxyl, hydroxyl, amino acids, etc., and exhibited 6–140fold increase in aqueous solubility when compared to paclitaxel. One of these prodrugs exhibited improved water solubility, better in vitro anticancer activity and significantly superior oral bioavailability in mice when compared to those of paclitaxel. Thus, we have identified a very promising lead compound for further optimization and evaluation as a potentially bioavailable water-soluble prodrug of paclitaxel.

Minnelide: A promising new therapy for ovarian cancer

Objectives: Minnelide (Minn) is a novel, water soluble prodrug of triptolide. The goal of this study was to evaluate the effectiveness of Minn on ovarian cancer using in vitro and in vivo models.

First enzymatic galactosylation of acyclic nucleoside drugs by β-galactosidase: Synthesis of water-soluble β-D-galactosidic prodrugs

Acyclic nucleoside analogs constitute an important group of antiviral agents. However, these nucleoside drugs suffer from poor water solubility and low oral bioavailability in the clinic use. In the present work, the enzymatic synthesis of the water-soluble galactosidic prodrugs of acyclic nucleosides by using bovine liver β-galactosidase was described. In the enzymatic transgalactosylation between acyclovir (ACV) and o-nitrophenyl β-galactopyranoside (oNPGal), the optimum enzyme dosage, buffer pH, temperature and molar ratio of ACV to oNPGal were 0.225 U/mL, 7.0, 40°C and 2.5, respectively, under which the initial reaction rate and the yield reached 0.40 mM/h and 29%, respectively. In addition, this enzyme could accept ganciclovir (GCV) and penciclovir (PCV) as substrates, affording the corresponding 4’-β-galactosylated derivatives with the yields of 26% and 71%, respectively.

The antitumor activity of a red alga polysaccharide complexes carrying 5-fluorouracil

Porphyran is a sulfated galactan isolated from red algae Porphyra haitanensis, and have been reported to have many kinds of biological activities such as antitumor activity. In order to provide a water-soluble macromolecule prodrug of 5-Fu showing slow release of 5-Fu and reducing side-effect, we carried out fixation of 5-Fu to porphyran at 6-position. In this study, the antitumor and immunomodulation activities of low MW porphyran carrying 5-Fu on transplanted S180 tumor mice were studied. Weight of immune organ, proliferation ratio of lymphocyte concentration of TNF-α and NO from the transplanted S180 tumor mice were also determined. Results indicated that the conjugate could enhance antitumor activity of 5-Fu and improve immunocompetence damaged by 5-Fu.

Design, synthesis, and structure-activity relationship studies of novel thioether pleuromutilin derivatives as potent antibacterial agents.

A series of novel thioether pleuromutilin derivatives incorporating various heteroaromatic substituents into the C14 side chain have been reported. Structure-activity relationship (SAR) studies resulted in compounds 52 and 55 with the most potent in vitro antibacterial activity among the series (MIC = 0.031-0.063 μg/mL). Further optimization to overcome the poor water solubility of compound 55 resulted in compounds 87, 91, 109, and 110 possessing good in vitro antibacterial activity with increased hydrophilicity. Compound 114, the water-soluble phosphate prodrug of compound 52, was also prepared and evaluated. Among the derivatives, compound 110 showed moderate pharmacokinetic profiles and good in vivo efficacy in both MSSA and MRSA systemic infection models. Compound 110 was further evaluated in CYP450 inhibition assay and displayed intermediate in vitro inhibition of CYP3A4.

Carboxymethylcellulose–tetrahydrocurcumin conjugates for colon-specific delivery of a novel anti-cancer agent, 4-amino tetrahydrocurcumin

Several curcumin derivatives are now becoming increasingly of interest because of their bioactive attributes, especially their action as antioxidants and anti-carcinogenic activities. Tetrahydrocurcumin (THC), an active metabolite of curcumin, was selected to be a proper starting material for the work presented here as it is stable in physiological pH and has the typical pharmacological properties of curcumin. We have now reported that novel synthesized water-soluble polymeric macromolecule prodrugs can specifically deliver the drug to the colon. To study the drug loading and drug release, THC was conjugated with a hydrophilic polymer, carboxymethylcellulose (CMC) with the degree of substitution (DS) values of 0.7 and 1.2. THC was also attached to two different spacers including p-aminobenzoic acid (PABA) and p-aminohippuric acid (PAH) via an azo bond that was cleaved by the azoreductase activities of colonic bacteria. The novel active molecule, 4-amino-THC, was readily released from the conjugates in the colon (>62% within 24h) with only very small amounts released in the upper GI tract (<12% over 12h). The polymer conjugates showed chemical stability at various pH values along the gastrointestinal tract and increased water solubility of up to 5mg/mL. 4-Amino-THC demonstrated cytotoxic ability against the human colon adenocarcinoma cell lines (HT-29) with an IC50 of 28.67±1.01μg/mL, and even greater selectivity (∼4 folds) to inhibit HT-29 cells than to normal human colon epithelial cell lines while curcumin was a non-selective agent against both cell lines. Our study has demonstrated that the use of THC–CMC conjugates may be a promising colon-specific drug delivery system with its sustained release in the colon to be an effective treatment for colonic cancer.

Recent progress on C-4-modified podophyllotoxin analogs as potent antitumor agents.

Podophyllotoxin (PPT), as well as its congeners and derivatives, exhibits pronounced biological activities, especially antineoplastic effects. Its strong inhibitory effect on tumor cell growth led to the development of three of the most highly prescribed anticancer drugs in the world, etoposide, teniposide, and the water-soluble prodrug etoposide phosphate. Their clinical success as well as intriguing mechanism of action stimulated great interest in further modification of PPT for better antitumor activity. The C-4 position has been a major target for structural derivatization aimed at either producing more potent compounds or overcoming drug resistance. Accordingly, numerous PPT derivatives have been prepared via hemisynthesis and important structure-activity relationship (SAR) correlations have been identified. Several resulting compounds, including GL-331, TOP-53, and NK611, reached clinical trials. Some excellent reviews on the distribution, sources, applications, synthesis, and SAR of PPT have been published. This review focuses on a second generation of new etoposide-related drugs and provides detailed coverage of the current status and recent development of C-4-modified PPT analogs as anticancer clinical trial candidates.

An Improved Design of Water-Soluble Propofol Prodrugs Characterized by Rapid Onset of Action

Phosphate ester prodrugs of propofol (fospropofol, HX0969W) were designed to avoid the unsatisfactory water solubility of the parent drug. However, in previous clinical trials, there were reported prodrug side effects such as paresthesia and pruritus. The accumulation of a phosphate ester component was found to be the main culprit. To exclude this potential risk, we designed 2 amino acid propofol prodrugs (HX0969-Gly-F3, HX0969-Ala-HCl) based on the lead compound (HX0969) by introducing the amino acid group into the structures of the propofol prodrugs. We hypothesized that the improved propofol prodrugs could not only eliminate those adverse effects but also retain their rapid action and good water solubility. The lead compound HX0969 was synthesized by the sodium borohydride-iodine system. HX0969W, HX0969-Gly-F3, and HX0969-Ala-HCl were synthesized from HX0969. The solubility of fospropofol, HX0969W, HX0969-Gly-F3, and HX0969-Ala-HCl in normal saline was tested. The bioconversions from those prodrugs to propofol in different physiological media (rat plasma, rhesus monkey plasma, and rat hepatic microsomes) were determined in vitro. An in vivo test in the rats was performed to measure the 50% effective dose (ED50) of the 4 propofol prodrugs. Their action onset time and duration time were also measured after their equipotent doses were given. (1) The water solubility of fospropofol, HX0969W, HX0969-Gly-F3, and HX0969-Ala-HCl was 461.46 ± 26.40 mg/mL, 189.45 ± 5.02 mg/mL, 49.88 ± 0.58 mg/mL, and 245.99 ± 4.83 mg/mL, respectively; (2) The hydrolysis tests in both the rat plasma and the rhesus monkey plasma revealed that the 2 amino acid prodrugs released propofol to a greater extent at a more rapid rate than the 2 phosphate prodrugs during the testing period of 5 hours. All 4 prodrugs released propofol rapidly in the presence of rat hepatic enzymes; (3) Compared with the previous prodrugs (fospropofol, HX0969W), the 2 novel compounds (HX0969-Gly-F3, HX0969-Ala-HCl) had a much shorter onset time when a much lower dose was given. Application of the amino acid group to the propofol prodrug can make the prodrug have good water solubility and a more rapid onset of action. In rat plasma, the 2 improved amino acid prodrugs (HX0969-Ala-HCl, HX0969-Gly-F3) had a more rapid rate of propofol release than the 2 phosphate ester prodrugs (fospropofol, HX0969W). The in vivo tests showed that HX0969-Ala-HCl and HX0969-Gly-F3 given IV could have a more rapid onset of action in a smaller dose than fospropofol and HX0969W. This novel design can enhance the efficiency of prodrugs converting to propofol.

A Scalable One-Pot Process for the Synthesis of Florfenicol Phosphodiester

A practical and scalable one-pot process for the preparation of florfenicol phosphodiester (3), a new water-soluble prodrug of florfenicol (1), has been developed by adopting the phosphorylating system of POCl3/pyridine/CH3CN. The yield of 3 was 80.72%, and its HPLC purity reached as high as 99.20%, while the content of the maximum impurity was reduced to 0.28% under the optimum conditions. The present process has proven to be reliable on 500-g and 4-kg scale in the pilot plant.

Spectroscopic characterization of both aqueous and solid-state diacerhein/hydroxypropyl-β-cyclodextrin inclusion complexes

Diacerhein, a poorly water soluble antirheumatic prodrug, was spectroscopically characterized to form inclusion complexes with hydroxypropyl-β-cyclodextrin (HPβCD) in both aqueous solution and in solid phase. Complexation with the hydrophilic carriers was used to improve the solubility and dissolution rate of the compound. The kinetics of the prodrug degradation to the active rhein in aqueous buffer solution were also investigated as a function of HPβCD concentration. The solid complexes prepared by different methods such as physical mixture, kneading, co-evaporation method and freeze dried method in 1:1M ratio, were characterized by DSC and FTIR. The dissolution profiles of solid complexes were determined and compared with diacerhein alone and their physical mixture, in the simulated intestinal fluid at 37°C. The accurate molecular spectroscopic characterization of diacerhein in the presence of different amounts of aqueous cyclodextrins was essential to determine the correct binding constants for the diacerhein/HPβCD system. The binding constants were also validated by UV spectrometry and HPLC procedure in order to compare the values from the different methods. Higuchi–Connors phase solubility method has proved not suitable when either the free or/and the complexed prodrug degrade in aqueous solution.

The American Pancreatic Association/Hirshberg Foundation Symposium Celebrating the 10th Anniversary of the Seed Grant Program

The Hirshberg Foundation for Pancreatic Cancer Research was founded by Agi Hirshberg in 1997, following her husband Ronald Hirshberg’s 8-month, 7-day battle with the disease. (http://www.pancreatic.org/). At the time, the Hirshberg family viewed pancreatic cancer as the ‘‘unknown enemy’’ (http:// www.pancreatic.org/site/c.htJYJ8MPIwE/b.8276835/k.66CB/ Agi_Hirshbergs_Story.htm). In the years since Ronald Hirshberg’s death, Agi Hirshberg has made it her mission to unmask the unknown for others facing the same enemy. When patients present with a new diagnosis of pancreatic cancer, most are already in an advanced stage of the disease. Pancreatic cancer is resistant to most chemotherapeutic agents and radiotherapy. These factors combine to make pancreatic cancer a highly lethal disease, and according to the National Cancer Institute (NCI) 2013 estimates, pancreatic cancer was diagnosed in approximately 45,220 US citizens, and some 38,460 died of the disease. 1 The Annual Report to the Nation on the Status of Cancer, 1975Y2009, shows that overall cancer death rates continued to decline in the United States among both men and women, among all major racial and ethnic groups, and for all of the many common cancer sites, including lung, colon and rectum, female breast, and prostate. However, this trend does not hold true for pancreatic cancer. The report demonstrates that death rates continued to increase during the latest time period (2000 through 2009) for pancreatic cancer. 2 Only about 23% of patients with cancer of the pancreas will still be living 1 year after diagnosis, and only about 4% will survive 5 years. Even for those diagnosed with pancreatic cancer that has not spread to other organs or systems, the overall 5-year survival rate approaches only 15%. The Hirshberg Foundation’s vision is to advance pancreatic cancer research and provide information, resources, and support to pancreatic cancer patients and their families. The mission of the Foundation is as follows: & To find a cure for pancreatic cancer in honor of Ron Hirshberg and the thousands of people who are diagnosed with this disease each year. & To create a premier Pancreatic Cancer Center where all needs of pancreatic cancer patients can be met in one location with the most advanced treatment options. & To be recognized as a patient support reference source for

ChemInform Abstract: Medicinal Chemistry and Chemical Biology of Diketopiperazine‐Type Antimicrotubule and Vascular‐Disrupting Agents

AbstractReview: 63 refs.