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Cyclin-dependent kinase 1 (CDK1), an enzyme participating in the regulation of the cell cycle, constitutes a possible target in the search for new antitumor agents. Starting from the purine derivative olomoucine and following a structure-based approach, potent inhibitors of this enzyme were rapidly identified. The molecular modeling aspects of this work are described.

Novel 2,6,9-substituted purine derivatives represent a class of potent and selective inhibitors of CDK1/cyclinB. The synthesis, SAR and biological profile of selected compounds are described.

On the basis of previously described X-ray studies of an enzyme/aza-dipeptide complex,8 aza-dipeptide analogues carrying N-(bis-aryl-methyl) substituents on the (hydroxethyl)hydrazine moiety have been designed and synthesized as HIV-1 protease inhibitors. By using either equally (12) or orthogonally (13) protected dipeptide isosteres, symmetrically and asymmetrically acylated aza-dipeptides can be synthesized. This approach led to the discovery of very potent inhibitors with antiviral activities (ED50) in the subnanomolar range. Acylation of the (hydroxethyl)hydrazine dipeptide isostere with the L-tert-leucine derivative 29 increased the oral bioavailability significantly when compared to the corresponding L-valine or L-isoleucine derivatives. The bis(L-tert-leucine) derivatives CGP 75355, CGP 73547, CGP 75136, and CGP 75176 combine excellent antiviral activity with high blood concentration after oral administration. Furthermore, they show no cross-resistance with saquinavir-resistant strains and maintain activity against indinavir-resistant ones. Consequently they qualify for further profiling as potential clinical candidates.

Protein binding can impair the potency of human immunodeficiency virus (HIV) protease inhibitors. Therefore, the activity of a novel compound, CGP 61755, was studied in the absence or presence of alpha1-acid glycoprotein (alpha1AGP). In MT-2 cells, the activity loss was 4-fold (EC90 without alpha1AGP, 29 nM vs. 122 nM with alpha1AGP). In primary lymphocytes, the loss was 8-fold (EC90, 45 nM vs. 364 nM). In identical experiments, the activity loss in MT-2 cells and lymphocytes was 2- and 3-fold, respectively, for indinavir, 11- and 10-fold for saquinavir, and 11- and 48-fold for ritonavir. For SC-52151, a 17-fold loss was seen in MT-2 cells, whereas no EC90 with alpha1AGP was reached in lymphocytes. This study demonstrates that the impact of alpha1AGP on in vitro activity varies greatly among different HIV protease inhibitors. The magnitude of such differences is greater in human lymphocytes than in a standard cell line.

A series of aza-peptide analogs with a (hydroxyethyl)hydrazine isostere has been synthesized as HIV-1 protease inhibitors using a simple synthetic scheme. Structure-activity studies based on the X-ray of a previously described inhibitor-enzyme complex led to potent inhibitors with antiviral activity in the low-nanomolar range. The S-configuration of the transition-state hydroxyl group was preferred in this series. Small modifications of the P2P3 and P2'P3' substituents had little effect on enzyme inhibition but greatly influenced the pharmacokinetic profile. As a result of these studies, the symmetrically acylated compound 8a and its close analog 24a bearing a methyl carbamate in P3 and an ethyl carbamate in P3' position were identified as potent inhibitors with plasma concentrations exceeding antiviral ED50 values 150-fold following oral application in mice.

A series of potent HIV-protease inhibitors has been prepared. Several of the newly synthesized compounds showed high plasma levels after oral administration to animals. Based on the overall biological profile, CGP 61755 was chosen for further preclinical evaluation. For this compound, a 10 step synthesis potentially suitable for large scale production was developed.

The pharmacokinetics and body distribution of zinc phthalocyanine (ZnPc) intravenously administered in liposomes composed of ZnPc, 1-palmitoyl-2-oleoylphosphatidylcholine (POPC), and 1,2-dioleoylphosphatidylserine (OOPS) (1:90:10 or 1:70:30 w/w) to tumor (Meth A sarcoma) bearing mice were studied. It was found that aggregation of ZnPc in the liposomes (i) increases the clearance rate of the dye from plasma, (ii) lowers the maximal dye concentration in tumor tissue, and (iii) increases the maximal dye concentration in the liver. In addition, aggregated dye is hardly eliminated from the liver and monomeric dye is eventually completely eliminated from this organ. Liposomes in the size range of 48-123 nm, containing the dye with the same aggregation state, showed the same pharmacokinetics and body distribution of the dye. The PS-content of the ZnPc liposomes (POPC alone versus POPC/OOPS 7:3) did not influence tumor, liver, and plasma pharmacokinetics during the studied time intervals. Free flow electrophoretic analysis showed in lyophilisates of ZnPc liposomes containing aggregated ZnPc the presence of two distinct populations differing in size, aggregation state of the dye, and PC/PS and ZnPc/phospholipid ratio. The liposomal formulation with monomeric ZnPc has a compositional homogeneity and demonstrated selectivity and reached high uptake in tumors, 48 h after intravenous administration and appears promising for photodynamic therapy.

A series of 3-acylbenzamidine (amidino)hydrazones 7a-h, the corresponding (hetero)aromatic congeners 7i-p, and 3,3'-bis-amidino-biaryls 25a-e were synthesized. The hydrazones 7a-p were prepared by conversion of the corresponding acyl nitriles 1a,c-d,i,n-p to the imido esters 3a,c-d,i and the amidines 5a,c-d,h-i, followed by a reaction with aminoguanidine, or vice versa. Similarly, the biaryl 3,3'-dinitriles 23a-e were converted, via the imino esters 24a-c or the imino thioesters 27d-e, to the diamidines 25a-e. These new products are conformationally constrained analogues of methylglyoxal bis(guanylhydrazone) (MGBG). They are up to 100 times more potent as inhibitors of rat liver S-adenosylmethionine decarboxylase (SMDC) and generally less potent inhibitors of rat small intestine diamine oxidase (DAO) than MGBG. Some of these SAMDC inhibitors, e.g., compounds 7a, 7e, 7i, 25a, and 25d, have shown antiproliferative effects against T24 human bladder carcinoma cells. These products, whose structure-activity relationships are discussed, are of interest as potential anticancer agents and drugs for the treatment of protozoal and Pneumocystis carinii infections.

Novel 2,6,9-substituted purine derivatives represent a class of potent and selective inhibitors of CDK1/cyclinB. The synthesis, SAR and biological profile of selected compounds are described.

IGF-IR-mediated signaling promotes survival, anchorage-independent growth, and oncogenic transformation, as well as tumor growth and metastasis formation in vivo. NVP-AEW541 is a pyrrolo[2,3-d]pyrimidine derivative small molecular weight kinase inhibitor of the IGF-IR, capable of distinguishing between the IGF-IR (IC50 = 0.086 microM) and the closely related InsR (IC50 = 2.3 microM) in cells. As expected for a specific IGF-IR kinase inhibitor, NVP-AEW541 abrogates IGF-I-mediated survival and colony formation in soft agar at concentrations that are consistent with inhibition of IGF-IR autophosphorylation. In vivo, this orally bioavailable compound inhibits IGF-IR signaling in tumor xenografts and significantly reduces the growth of IGF-IR-driven fibrosarcomas. Thus, NVP-AEW541 represents a class of selective, small molecule IGF-IR kinase inhibitors with proven in vivo antitumor activity and potential therapeutic application.

This work describes the development of an organic solvent dilution method suitable for the large scale manufacturing of small unilamellar liposomes containing the water-insoluble photosensitizer zinc phthalocyanine in the monomeric state. N-Methyl pyrrolidone (NMP)/tert-butyl alcohol was selected as water miscible organic phase in which the phospholipids 1-palmitoyl, 2-oleoylphosphatidylcholine (POPC), and 1,2-dioeloylphosphatidylserine (OOPS) and the dye were dissolved. This organic phase was mixed with an excess of a water phase using a dynamic mixing device, yielding reproducibly unilamellar liposomes with a mean size of 50-150 nm as measured with quasielastic light scattering. After concentration, the organic solvents were efficiently removed by cross-flow filtration. The liposomes were then sterile filtered and freeze-dried. A method to measure the aggregation state of the dye in the liposomes was developed. A stable lyophilized formulation containing monomeric liposomal ZnPc could be obtained by using a solution of ZnPc in NMP (2 mg/mL) and ZnPc/phospholipid (1:100 w/w ratio) and performing concentration and dialysis at 4 degrees C and lyophilization in presence of a mixture of lactose and phospholipid (5:1 w/w ratio).

Zinc(II)-phthalocyanine (Zn-Pc) was chosen for development as a second-generation photosensitizer for photodynamic therapy (PDT) of tumors and for benign conditions because of its advantageous chemical and photophysical properties. Zn-Pc displayed good selectivity for malignant tissue in pharmacokinetic studies with Meth-A-sarcoma-bearing BALB/c mice when injected in a dose of 0.125 mg/kg, delivered by CGP 55 847. Intravenous doses of Zn- Pc ranging from 0.032 to 0.375 mg/kg caused tumor necrosis and, subsequently, cure of Meth-A-sarcoma-bearing mice when phototreatment was performed 48 hours after injection of CGP 55 847. Intravenous injection of Zn-Pc into hairless mice in doses ranging from 0.1 to 1.0 mg/kg caused dose- and time-dependent phototoxicity. We conclude that the promising pharmacological properties of liposomally delivered Zn-Pc, along with its advantageous chemical and photophysical properties, warrant the development of CGP 55 847 as a candidate drug for photodynamic therapy of tumors in humans.

The pharmacokinetic and phototherapeutic properties of new phthalocyanines with Ge(IV) or Si(VI) as the central metal ion and cholesterol, cholestan or long-chain fatty acids residues as axial ligands to the central ion have been studied in tumor-bearing mice. The new photosensitizers were selectively taken up by and relatively quickly released from the tumors. Except for Si(IV)-Pc, which showed a comparably high selectivity for tumor versus peritumoral tissue, all Ge(IV)-Pc were less selective than liposomal Zn-Pc (CGP 55847). However, all the new compounds showed excellent phototherapeutic efficiency at very low drug and light doses in studies in Meth-A-sarcoma-bearing mice.© (1994) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

A phthalocyanine derivative with two cholesterol moieties as axial ligands to the central Ge(IV) ion efficiently photosensitizes the oxidative modification of L-tryptophan. Administration of liposome-bound GePc to Balb/c mice bearing a MS-2 fibrosarcoma yields a quantitative release of the dye to serum lipoproteins, followed by a selective accumulation in the tumor as well as a low content in the skin. At 24 h after injection of 0.76 mg/kg GePc, the tumor was irradiated with 600 - 700 nm light; tumor necrosis appeared in all treated mice as a consequence of extensive damage of cellular and stromal elements.© (1994) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Liposomes were prepared containing zinc-phthalocyanine (ZnPc). The composition was ZnPc/POPC/OOPS (1:90:10 w/w /w). The phospholipids (PL) were dissolved in t-butanol at 50 degree(s)C under magnetic stirring and mixed with ZnPc, dissolved in NMP for two hours in an ultrasonic bath at 80 degree(s)C. This mixture (50 degree(s)C) was diluted with lactose- NaCl solution (9.475% lactose, 0.027% NaCl) at 4 degree(s)C using a dynamic mixer. The collected liposomal suspension was concentrated first, to 20 mg PL/ml suspension and then the organic solvents were removed by tangential flow filtration (CentrasetteR) against a ten fold volume of lactose-NaCl solution. After sterile filtration the liposomal suspension was freeze-dried for 24 hours.© (1994) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

A series of new octakis-substituted Germanium-phthalocyanines for use in photodynamic therapy of tumors has been synthesized. Starting from 1,4-dialkoxy-2,3-dicyano-benzene the metal-free octakis-alkoxy-phthalocyanine 13 was prepared. The metallation to the corresponding octakis-alkoxy-GeCl2-phthalocyanine 15 was done with a GeCl4-DMF complex. Alkaline hydrolysis gave quantitatively the octakis-alkoxy-Ge(OH)2- phthalocyanine 16. By substitution of the hydroxy groups with alcohols, thiols and silanols the axially disubstituted phthalocyanines were obtained. The most important photophysical properties for PDT (Q-bands, singlet oxygen quantum yields and (Phi) f) are reported.© (1994) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

The 13C-NMR. spectra of a number of colchicine derivatives are given comprising examples of the normal series (4→10), iso series (11→16) and colchicine series (17), which were either reported in the literature or obtained by partial synthesis or degradation reactions. The 13C-NMR. assignments were made by comparisons with known compounds and selective single-frequency offresonance decoupling experiments. Selective proton decoupling experiments have also allowed assignments of the H—C(11) and H—C(12) protons of the iso and colchicine series.

A synthesis of the novel C10H16 hydrocarbon 2,5-trimethylenenorbornane (tricyclo[5.3.0.03,9]decane, 1), one of the 19 members of the ‘adamantaneland’, and its Lewis-acid-catalyzed rearrangement is described.

A synthesis of twista-4,9-diene (17) from tricyclo[4.3.1.03,8]dec-4-en-10-one (2) is described.

[2+2]-Cycloaddition of ‘Maleic Isoimides’ with Ketenes and Reactions of Spiro-b-lactams to Muconic and Tetramic Acids The [2 + 2]-cycloaddition of iminolactones of type 2 (‘maleic isoimides’) with various ketenes affords spiro-b-lactams 4–6. These highly functionalized compounds react with CH3ONa giving ketoadipinic acid derivatives 12 and/or pyrrolidinediones 7, depending on the reaction temperature and the nature of substituents.

(+)-(1S, 3S, 6S, 8S)-and (−)-(1R, 3R, 6R, 8R)-4, 9-Twistadiene: Synthesis and Absolute Configuration A synthesis and the determination of the absolute configuration of (+)-(1S, 3S, 6S, 8S)- and (−)-(1R, 3R, 6R, 8R)-4, 9-twistadiene ((+)- and (−)-4, respectively) is described. Their chiroptical properties are compared with those of saturated twistane ((+)- and (−)-5) as well as with those of the unsaturated and saturated 2, 7-dioxatwistane analogs (+)- and (−)-9, and (+)- and (−)-10, respectively, which also are compounds of known absolute configurations.

Cycloaddition of Chlorosulfonylisocyanate to ‘Maleic Isoimides’ Cycloaddition reactions of chlorosulfonylisocyanate to ‘maleic isoimides’ are described. The not expected multifunctional (2:1)-adducts 2 were converted to the crystalline compounds 3, whose structures were resolved by X-ray analysis.

N-Deacetylcolchiceine (7), readily available from colchicine (1), was converted into N-trifluoroacetyl-deacetylcolchiceine (8). Methylation of 8 with methyl iodide in the presence of potassium carbonate afforded a mixture of N-trifluoroacetyl-demecolcine (10) and its isomer 11. The mixture of 10 and 11 was detrifluoroacetylated and separated by chromatography to afford demecolcine (2) and isodemecolcine (12). A more practical route to 2 started with 8, and gave N-trifluoroacetyl-deacetylcolchicine (13) and its isomer 14 after O-methylation with diazomethane. N-Methylation of 13 and 14 with methyl iodide and potassium carbonate afforded 10 and 11. The overall yield in the conversion of colchicine (1) into demecolcine (2) via7, 8 and 13 was 55%.

Synthese d'uraciles substitues et a partir de ces composes, preparation d'acides [uracilyl-1- ou -3 methyl]-2 penemecarboxyliques-3

Publisher Summary Studies of the modern chemistry of colchicine started soon after the discovery of its powerful action on cell division in plants and animals. This chapter primarily considers novel congeners, the application of modern physical methods to their structure determination, the chemistry of colchicine itself, and its conversion into minor alkaloids. Emphasis is given to the biological effects of colchicine, its mode of action, and the exploration of structural features which affect potency, binding to tubulin, and toxicity. The presence of tropolonic Colchicum alkaloids is limited to plants. The isolation and analysis of tropolonic Colchicum alkaioids is discussed, along with the results obtained by microbial and metabolic degradation of colchicine and analog. To investigate the metabolic transformation of colchicine in mammals, a modified Udenfriend redox system, known to simulate microsomal reactions, was used. This system is discussed in the chapter and other novel syntheses of colchicines are also discussed.

A series of potent antibacterial agents have been prepared. These agents are penems carrying a lactone ring in the C-2 position. Excellent activity against Gram-positive and Gram-negative organisms--except Pseudomonas aeruginosa--was found.

N-Deacetylcolchiceine (7), readily available from colchicine (1), was converted into N-trifluoroacetyl-deacetylcolchiceine (8). Methylation of 8 with methyl iodide in the presence of potassium carbonate afforded a mixture of N-trifluoroacetyl-demecolcine (10) and its isomer 11. The mixture of 10 and 11 was detrifluoroacetylated and separated by chromatography to afford demecolcine (2) and isodemecolcine (12). A more practical route to 2 started with 8, and gave N-trifluoroacetyl-deacetylcolchicine (13) and its isomer 14 after O-methylation with diazomethane. N-Methylation of 13 and 14 with methyl iodide and potassium carbonate afforded 10 and 11. The overall yield in the conversion of colchicine (1) into demecolcine (2) via7, 8 and 13 was 55%.

A synthesis of twista-4,9-diene (17) from tricyclo[4.3.1.03,8]dec-4-en-10-one (2) is described.