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An oxidative intermolecular enolate heterocoupling reaction was employed for the synthesis of anti-2,3-disubstituted succinic acid mono- and differentially protected diesters. Tactical approaches to access all the diastereomers are discussed. The method was applied to the synthesis of a potent anticancer agent, BMS-906024.

A series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure-activity and structure-solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions.

Generation of imino-quinone methide type intermediates from 2-aminothiazole-5-carbinols using alkylsulfonic acids in nitromethane followed by trapping with a wide range of nucleophiles effects C-C, C-O, C-N, C-S, and C-P bond formation.

3-(Benzimidazol-2-yl)-pyridine-2-one-based ATP competitive inhibitors of Insulin-like Growth Factor 1 Kinase (IGF-IR) were optimized for reduced Cyp3A4 inhibition and improved oral exposure. The use of malonate as methyl anion synthon via S(N)Ar reaction and double decarboxylation under mild conditions is demonstrated.

The insulin-like growth factor I receptor (IGF-IR) is a transmembrane tyrosine kinase that is essential to growth and development and also thought to provide a survival signal for the maintenance of the transformed phenotype. There has been increasing interest in further understanding the role of IGF-I signaling in cancer and in developing receptor antagonists for therapeutic application. We describe herein a novel animal model that involves transgenic expression of a fusion receptor that is constitutively activated by homodimerization. Transgenic mice that expressed the activated receptor showed aberrant development of the mammary glands and developed salivary and mammary adenocarcinomas as early as 8 weeks of age. Xenograft tumors and a cell line were derived from the transgenic animals and are sensitive to inhibition by a novel small-molecule inhibitor of the IGF-IR kinase. This new model should provide new opportunities for further understanding how aberrant IGF-IR signaling leads to tumorigenesis and for optimizing novel antagonists of the receptor kinase.

A series of fluoroglycosylated fluoroindolocarbazoles was examined with respect to their topoisomerase I activity, cytotoxicity, and selectivity. The lead clinical candidate from this series, BMS-250749, displays broad spectrum antitumor activity superior to CPT-11 against some preclinical xenograft models, including curative antitumor activity against Lewis lung carcinoma.

A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.

Furoindoles 7 and 16 undergo smooth intramolecular Diels-Alder reactions to afford, after dehydration, hydrolysis, and oxidation, benzocarbazoles 11 and 21, respectively.

The atom economical synthesis of hydrogen halide salts of primary amines, directly from the corresponding halides, avoids the production of significant amounts of secondary amine side products, and requires only evaporation of the solvent to access the products in yields generally greater than 90%. The procedure uses microwave irradiation in 7 M ammonia in methanol (Aldrich) at 130 °C from 0.5 to 2.5 h and works on a variety of alkyl halides, as well as mesylates and tosylates. Benzylamines are obtained from benzyl halides without significant amounts of the secondary amine side products that result without microwave heating. Direct isolation of even highly volatile primary amines as their hydrogen halide salts makes the method ideal for use in parallel synthesis.

Etoposide Phosphate (BMY-40481) is synthesized semisynthetically from the clinically approved anticancer parent drug, etoposide (VP-16-213), and also from natural (−)-epipodophyllotoxin. Etoposide phosphate functions as a clinically active, water soluble prodrug of etoposide. The NDA for etoposide phosphate was filed in June, 1994.

A new class of guanidino prodrug is efficiently synthesized from an amine and an appropriate N,N′-bis(acyloxymethoxycarbonyl)-S-methylisothiourea. The N,N′-bis(acyloxymethoxycarbonyl)-S-methylisothiourea is readily prepared from S-methylisothiourea and the corresponding acyloxymethyl carbonochloridate in good yield. The N,N′-bis(acyloxymethyl carbamate) derivatives of the highly basic guanidino group serve as lipophilic, uncharged, esterase-activatable prodrugs of simple guanidine containing molecules.

Deoxyspergualin (DSG), a spermidinyl, alpha-hydroxyglycyl, 7-guanidinoheptanoyl peptidomimetic, shows immunosuppressive activity. In confirmation of a recent report that immobilized methoxyDSG selectively retains the heat shock protein Hsc70, we report here quantitative binding of DSG and analogs to both Hsc70 and the 90-kDa heat shock protein Hsp90. We have utilized affinity capillary electrophoresis to obtain Kd values for DSG and analogs, and stimulation of the ATPase activity of Hsc70 to obtain Km values for DSG, that are comparable and corroborative. Kd values are 4 microM for DSG binding to Hsc70 and 5 microM for DSG binding to Hsp90. Two active analogs, methoxy- and glycylDSG, bind with similar affinities. Glyoxylylspermidine and des(aminopropyl)DSG, two inactive metabolites, have much reduced affinity for Hsc70 and Hsp90. These data validate binding of these novel immunosuppressant agents to these molecular chaperones, at concentrations in the range of pharmacologically active doses, and indicate that further characterization of Hsc70 and/or Hsp90 as potential targets for DSG is warranted.

Therapeutic development of a targeted agent involves a series of decisions over additional activities that may be ignored, eliminated or pursued. This paper details the concurrent application of two methods that provide a spectrum of information about the biological activity of a compound: biochemical profiling on a large panel of kinase assays and transcriptional profiling of mRNA responses. Our mRNA profiling studies used a full dose range, identifying subsets of transcriptional responses with differing EC(50)s which may reflect distinct targets. Profiling data allowed prioritization for validation in xenograft models, generated testable hypotheses for active compounds, and informed decisions on the general utility of the series.

The E-ring 3′,4′,5′-trihydroxy etoposide analog 3 of the clinical antitumor agent etoposide 1 was synthesized from the corresponding etoposide ortho-quinone 2 . This analog is twice as potent as etoposide in its ability to elicit topoisomerase II mediated DNA double strand breaks. However, our in vitro cytotoxicity assay, using human colon tumor cells grown in culture, and our in vivo P388 murine leukemia screen reveal considerable loss of potency and/or activity vis-a-vis etoposide.

Tritium labeled (±) 15-deoxyspergualin, (±)-7-[(aminoiminomethyl) amino]-N-[2-[[4-[(3-aminopropyl) amino]butyl]amino]-1-hydroxy-2-oxoethyl][4,5-3H2]heptanamide trihydrochloride was prepared from the acid catalyzed condensation of 7-guanidino[4,5-3H2] heptanamide hydrochloride and glyoxyloylspermidine dihydrochloride in a total yield of 14.5%. The radiochemical purity was determined to be 91.1% and 95.4% on two different HPLC systems.

We record the first synthesis of rocaglamide, assignment of its absolute stereochemistry, and the development of a novel oxidative cyclization to create the dihydrobenzofuran ring

Seven examples of the novel 4H-furo[3,4-b]indole ring system (3-9)-a stable, synthetic analogue of indole-2,3-quinodimethane have been synthesized in 6-8 steps from simple indoles in overall yiels of 21-28%. These 4H-furo[3,4-b]indoles undergo Diels-Alder reactions with several dienophiles (dimethyl acetylenedicarboxylate N-phenylmaleimide, benzyne), inclunding ethyl acrylate, witch reacts regiospecifically with furoindole 4 to afford a single carbazole ester (59). This result, predicted by molecular orbital calculations, was used to design and execute a regiospecific Diels-Alder synthesis of the antitumor alkaloid ellipticine (63)

A new class of guanidino prodrug is efficiently synthesized from an amine and an appropriate N,N′-bis(acyloxymethoxycarbonyl)-S-methylisothiourea. The N,N′-bis(acyloxymethoxycarbonyl)-S-methylisothiourea is readily prepared from S-methylisothiourea and the corresponding acyloxymethyl carbonochloridate in good yield. The N,N′-bis(acyloxymethyl carbamate) derivatives of the highly basic guanidino group serve as lipophilic, uncharged, esterase-activatable prodrugs of simple guanidine containing molecules.

Furoindoles 7 and 16 undergo smooth intramolecular Diels-Alder reactions to afford, after dehydration, hydrolysis, and oxidation, benzocarbazoles 11 and 21, respectively.

Generation of imino-quinone methide type intermediates from 2-aminothiazole-5-carbinols using alkylsulfonic acids in nitromethane followed by trapping with a wide range of nucleophiles effects C−C, C−O, C−N, C−S, and C−P bond formation.

The E-ring 4′-deshydroxy-4′-methyl analogs of the clinical antitumor agents etoposide and teniposide were synthesized from the corresponding 4′-triflates. These compounds display significant antitumor activity against murine P388 leukemia in vivo but are only 1/5 as cytotoxic against a human colon tumor cell line (HCT-116) grown in culture. These analogs also show inferior activity vis-a-vis etoposide and teniposide when evaluated for their ability to inhibit purified human topoisomerase II.

Seven examples of the novel 4H-furo[3,4-b]indole ring system (3-9)-a stable, synthetic analogue of indole-2,3-quinodimethane have been synthesized in 6-8 steps from simple indoles in overall yiels of 21-28%. These 4H-furo[3,4-b]indoles undergo Diels-Alder reactions with several dienophiles (dimethyl acetylenedicarboxylate N-phenylmaleimide, benzyne), inclunding ethyl acrylate, witch reacts regiospecifically with furoindole 4 to afford a single carbazole ester (59). This result, predicted by molecular orbital calculations, was used to design and execute a regiospecific Diels-Alder synthesis of the antitumor alkaloid ellipticine (63)

Reaction of etoposide ortho-quinone with primary amines results in products derived from transmination and reductive amination pathways. In contrast, thiols afford Michael adducts and/or thiol-quinone redox products.

The SAR of PXR transactivation by 3-(benzimidazol-2-yl)-pyridine-2-one based ATP competitive inhibitors of Insulin-like Growth Factor 1 Receptor kinase (IGF-1R) is discussed. Compounds without PXR transactivation, with in vivo antitumor activity, reduced protein binding and improved oral exposure are presented.

This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development.

BMY-40481-30 is a new, water-soluble derivative and probable prodrug of etoposide characterized by the presence of a phosphate group in position 4′ of the E ring of the etoposide molecule. The compound was only weakly cytotoxic in vitro and, consequently, an investigation of its antitumor activity was conducted in several murine and human tumor (xenograft) models. Etoposide was administered ip or po whereas BMY-40481-30 was given ip, po or iv. The potency of the derivative, when administered parenterally, as defined on the basis of maximum tolerated dose (MTD), was less than the parent compound on a weight (mg/kg) basis in some experiments but comparable to etoposide in other instances. Comparison at the MTD of the two compounds showed that BMY-40481-30 administered ip was as active as etoposide against ip P388 leukemia. BMY-40481-30 given iv was more active than etoposide given ip in two of five experiments versus iv P388 leukemia, but the two compounds were comparably active in the other three studies. Of particular interest was the finding that the derivative was more active than the parent compound at many of the comparable (on a mg/kg basis) dose levels of both evaluated po versus iv P388 leukemia; MTD levels were not achieved, and hence not compared, for either compound using the po route of administration. Both etoposide and BMY-40481-30 yielded comparable maximum effects against ic P388 leukemia, ic L1210 leukemia, and sc B16 melanoma, but etoposide was more efficacious versus sc M5076 sarcoma. In addition to murine tumors, the HCT-116 human colon carcinoma was tested in a subrenal capsule model in athymic (nude) mice; both compounds demonstrated similar tumor inhibitory effects. Lastly, the human lung carcinomas, LX-1 and H2981, implanted sc into nude mice, showed either equivalent sensitivity to etoposide and BMY-40481-30, or a slightly enhanced sensitivity to the parent compound, in several experiments performed. BMY-40481-30 is a novel derivative and probable prodrug of etoposide with excellent solubility in water and antitumor activity generally comparable to that of the parent compound as demonstrated in several preclinical models.

A series of IGF-1R inhibitors is disclosed, wherein the (m-chlorophenyl)ethanol side chain of BMS-536924 (1) is replaced with a series of 2-(1H-imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl)ethanamine side chains. Some analogs show improved IGF-1R potency and oral exposure. Analogs from both series, 16a and 17f, show in vivo activity comparable to 1 in our constitutively activated IGF-1R Sal tumor model. This may be the due to the improved protein binding in human and mouse serum for imidazole 16a and the excellent oral exposure of pyrazole 17f.

The insulin-like growth factor receptor (IGF-IR) and insulin receptor are either overactivated and/or overexpressed in a wide range of tumor types and contribute to tumorigenicity, proliferation, metastasis, and drug resistance. Here, we show that BMS-554417, a novel small molecule developed as an inhibitor of IGF-IR, inhibits IGF-IR and insulin receptor kinase activity and proliferation in vitro, and reduces tumor xenograft size in vivo. In a series of carcinoma cell lines, the IC50 for proliferation ranged from 120 nmol/L (Colo205) to >8.5 μmol/L (OV202). The addition of stimulatory ligands was unnecessary for the antiproliferative effect in MCF-7 and OV202 cells. BMS-554417 treatment inhibited IGF-IR and insulin receptor signaling through extracellular signal-related kinase as well as the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased Akt phosphorylation at Ser473. At doses that inhibited proliferation, the compound also caused a G0-G1 arrest and prevented nuclear accumulation of cyclin D1 in response to LR3 IGF-I. In Jurkat T-cell leukemia cells, this agent triggered apoptotic cell death via the mitochondrial pathway. BMS-554417 was orally bioavailable and significantly inhibited the growth of IGF1R-Sal tumor xenografts in vivo. BMS-554417 is a member of a novel class of IGF-IR/insulin receptor inhibitors that have potential clinical applications because of their antiproliferative and proapoptotic activity in vitro and in vivo. (Cancer Res 2006; 66(1): 362-71)

[reaction: see text] Both 6'- and 4'-fluoro-glycosylated indolo[2,3-a]carbazoles are substrates for base-induced loss of fluorine as a leaving group from sp3 carbon. In the case of alpha-N-glycosylated substrate 3, loss of fluorine from the 6'-position leads to 3,6-anhydroglucose analogue 1. A novel N12,N13-bridged sugar analogue 2 results from loss of 4'-fluorine from beta-N-glycosylated analogue 4. Both analogues 1 and 2 display topo I inhibitory potencies similar to camptothecin.

We record the first synthesis of rocaglamide, assignment of its absolute stereochemistry, and the development of a novel oxidative cyclization to create the dihydrobenzofuran ring

The diynene lithium acetylide 5 adds to 2-siloxy-2-cyclohexenone 6 followed by silyl migration to produce ketone adduct 7 , an intermediate towards a simple Esperamicin core

The regioselective ortho-lithiation of 3-chloro (4), 3-fluoro (7), 3-bromo- (10), 2-chloro- (22), and 4-chloropyridine (25) with lithium diisopropylamide affords, after quenching with various electrophiles, the corresponding ortho-disubstituted pyridines in yields from 16-96%. Halogen-metal exchange between 4-iodo-3-chloropyridine (6a) and tert-butyllithium or n-butyllithium provides a convenient generation of 3,4-pyridyne (1), which is trapped in a Diels-Alder reaction with furan and 2,5-dimethylfuran to give 31 and 32 (24-38%)

A synthesis of the Strychnos dinklagei alkaloid 17-oxoellipticine ( 2 ) is described that illustrates the versatility of ketolactam 3 in the construction of dissimilar dialkyl-substituted pyridocarbazoles.

Regioselective ortho lithiation of 2-, 3-, and 4-halopyridines is achieved with lithium diisopropylamide (−78°, tetrahydrofuran) to afford, upon quenching with electrophilic reagents, 2,3- and 3,4-disubstituted pyridines in good to excellent yield.

Two anti-tumor monoclonal antibodies, L6 (anticarcinoma) and 1F5 (anti-B lymphoma), were covalently linked to alkaline phosphatase (AP), forming conjugates that could bind to the surface of antigen-positive tumor cells. The conjugates were capable of converting a relatively noncytotoxic prodrug, etoposide phosphate (EP), into etoposide--a drug with significant antitumor activity. In vitro studies with a human colon carcinoma cell line, H3347, demonstrated that while EP was less toxic than etoposide by a factor of greater than 100, it was equally toxic when the cells were pretreated with L6-AP, a conjugate that bound to the surface of H3347 cells. The L6-AP conjugate localized in H3347 tumor xenografts in nude mice and histological evaluation indicated that the targeted enzyme (AP) was distributed throughout the tumor mass. A strong antitumor response was observed in H3347-bearing mice that were treated with L6-AP followed 18-24 hr later by EP. This response, which included the rejection of established tumors, was superior to that of EP (P less than 0.005) or etoposide (P less than 0.001) given alone. The IF5-AP conjugate did not bind to H3347 cells and did not enhance the toxicity of EP on these cells in vitro. In addition, IF5-AP did not localize to H3347 tumors in nude mice and did not demonstrate enhanced antitumor activity in combination with the prodrug.