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WO1993001193A1 - Composes marins (alcaloides) utiles comme inhibiteurs du vih - Google Patents

Composes marins (alcaloides) utiles comme inhibiteurs du vih Download PDF

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Publication number
WO1993001193A1
WO1993001193A1 PCT/US1992/005517 US9205517W WO9301193A1 WO 1993001193 A1 WO1993001193 A1 WO 1993001193A1 US 9205517 W US9205517 W US 9205517W WO 9301193 A1 WO9301193 A1 WO 9301193A1
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Prior art keywords
compound
integer
hiv
compounds
group
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PCT/US1992/005517
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English (en)
Inventor
Shing Huey Mai
Vasant Kumar Nagulapalli
Ashok D. Patil
Alemseged Truneh
John W. Westley
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Smithkline Beecham Corporation
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Publication of WO1993001193A1 publication Critical patent/WO1993001193A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to novel marine alkaloids which inhibit HIV infectivity.
  • HIV-1 Human immunodeficiency virus type 1
  • This highly variable virus shows selective tropism for CD4 + cells which is determined by recognition of the HIV envelope glycoprotein gpl20 with the CD4 cell-surface receptor protein. The manner in which HIV infection leads to the slow but progressive decline in CD4 + cells has not been established.
  • an agent which antagonizes HIV in vitro azidothymidine (AZT)
  • AHT azidothymidine
  • antagonism of HIV is a therapeutic strategy for AIDS.
  • One approach to inhibit HIV infectivity is to antagonize the HIV/host- cell interaction. That is, to antagonize the virus from binding and/or entering a host cell.
  • the process of viral infection is initiated by the attachment of HIV to cells through a high affinity interaction between gpl20 and the CD4 receptor protein, located on the cell surface. Subsequent to that, the virus enters the host cell by fusion of the viral and cellular membranes.
  • virus-mediated cell fusion which is also initiated by the interaction of gpl20 with the CD4 receptor protein.
  • Cells infected with the HIV virus can express viral envelope proteins, ultimately detected on the infected-cell's surface.
  • gpl20 on the surface of infected cells can bind to CD4 on uninfected cells leading to the fusion and consequent formation of multinuclear giant cells (i.e., syncytiu ) .
  • This process is envisioned as a cell-cell equivalent of the binding and fusion events between HIV and an uninfected cell.
  • the present invention is a compound represented by the structure:
  • R2 is selected from the group consisting of hydrogen, hydroxy, lower alkyl (C1-C4 ) , lower alkenyl (C2-
  • p is an integer from 1-6; or a pharmaceutically acceptable salt thereof.
  • this invention is a compound represented by the structure:
  • R3 is selected from the group consisting of hydrogen, hydroxy, lower alkyl(C1-C ) , lower alkenyl(C2-
  • p is an integer from 1-6; or a pharmaceutically acceptable salt thereof.
  • this invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable ' carrier.
  • this invention relates to a method of inhibiting HIV infection which comprises administering to a patient a pharmaceutically effective amount of a compound isolated from the marine sponge Batzella, wherein said compound inhibits HIV infectivity in vitro.
  • This invention also relates to a process for preparing an HIV inhibitor which comprises extracting the marine organism Batzella with an organic solvent, separating the extract into fractions containing HIV antagonist activity, and purifying said extract to an essentially homogeneous compound which inhibits HIV infectivity in vitro.
  • FIG. 1 shows the mass spectral analysis of Compound
  • FIG. 2 shows the mass spectral analysis of Compound
  • FIG.3 depicts the results of a competitive ELISA assay (i.e., "Bind") wherein the binding inhibition of sT4 (also referred to as CD4) to immobilized recombinant HIV gpl20 is determined in the presence of the compounds of the invention.
  • FIG. 3 also depicts the cytotoxicity results (i.e., "Cyto") of the SupTl cell line (measured by the inhibition of ⁇ H-thymidine incorporation) in the presence of the compounds of the invention.
  • “Native” refers to those compounds in the present invention that were not chemically modified after their isolation.
  • “Dmp dvtv” refers to compounds of the present invention that were reacted with the compound 2,4-pentanedione.
  • “Cph dvtv” refers to compounds of the present invention that were reacted with the compound 1,2-cyclohexanedione.
  • the present invention relates to compounds which inhibit the interaction between HIV and the human cell- surface protein, CD4.
  • the invention relates to a class of alkaloids derived from marine sponges which inhibit HIV binding and/or subsequent fusion of HIV-infected cells and uninfected cells.
  • the compounds of this invention are isolated from the genus Batzella. More preferably, they are isolated from a newly discovered species of Batzella (herein referred to as Batzella sp.) identified by Dr. Rob Van Soest of the Institute of Taxonomic Zoology, University of Amsterdam.
  • Phylum Porif ra A sedentary, filter-feeding metazoan which utilizes a single layer of flagellated cells (choanocytes) to pump a unidirectional water current through its body.
  • the sponge body is isolated from the external environment by a perforated epithelium, one cell thick.
  • Both the internal - t - flagellated epithelium (the choanoderm) and the external epithelium (the pinacoderm) differ from other etozoan epithelium in that they lack a stable basement membrane. Between these two thin layers is a third region, the mesohyl, which can vary in composition and extent, but which always includes some mobile cells and some skeletal material.
  • Class Demospongiae Marine or freshwater sponges with a siliceous skeleton in which megascleres are usually either monaxons or tetraxons, a triaxon being present as a major spicule type in one subclass only.
  • the spicule skeleton can be supplemented or replaced by a spongin skeleton which is utilized either as a cementing element for the mineral skeleton, or to form fibers.
  • Some genera have lost all specialized skeletal components.
  • reproductive pattern whether oviparous or viviparous, and to the type of larva produced. Orders are defined on the type of megascleres and microscleres present, on the organization and composition of the skeleton and on the detail of reproductive patterns.
  • Subclass Ceractinomorpha Demospongiae in which the typical reproductive pattern is viviparous: most species for which reproductive sequences are known incubate parenchymella larvae.
  • the megascleres in the group are always monaxonid, triaenes are never present.
  • Microscleres are generally sigmoid or chelate never asterose.
  • Spongin is an almost universal component of the skeleton.
  • Poecilosclerida The largest and structurally most diverse order of the Demospongiae. Poecilosclerida are Ceractinomorpha with a skeleton which is always composed of a combination of spicule and spongin fiber. The megascleres are monactine or diactine with many curious structural variations. Spiny spicules are common. Both fiber and spicule skeletons can be complex and show a great regional differentiation. Microsclere types are varied. The larvae are parenchymelle with incomplete ciliation, the posterior pole is always bare, and anterior and posterior poles may show differential pigmentation.
  • megascleres are monactine or diactine, have a fasciculate arrangement, and are organized into reticulate or plumoreticulate tracts provided with more or less spongin.
  • the megascleres are uniform in size and shape throughout the sponge, but included in some genera with ectosomal megascleres smaller than those of the choanosome.
  • Microscleres are sigmas and chelas of varied form
  • Genus Batzella Esperiopsidae with a reduced, loosely plumose skeleton of strongyles (tornotes) ; no ectosomal skeleton; no microscleres.
  • Batzella sp. The newly discovered organism Batzella sp. is very similar to the Great Barrier Reef Sponge Batzella frutex (see, Pulitzer-Finali, "Some new or little-known sponges from the Great Barrier Reef of Australia", Boll Mus 1st Biol Univ Genova f ⁇ :87-141 (1982)). It is found in the Caribbean Sea as further described in the Examples section. Moreover, once the location is known, Batzella sp. can be collected and used to isolate the compounds of the present invention.
  • the compounds of the present invention can be extracted into an organic solvent and then further purified.
  • solvents are known to one skilled in the art.
  • the compounds of the invention can be extracted into methyl alcohol, ethyl alcohol, dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetone and the like.
  • Preferred solvents are methyl alcohol or ethyl acetate.
  • the extraction is limited to just one solvent. More preferably, it is a two-solvent extraction, using two miscible solvents, e.g., methyl alcohol and 1,2-dichloroethane to extract the compounds of the present invention. If necessary. the extract may be desalted by column chromatography.
  • a nonionic polymeric resin such as XAD-2 is used.
  • the chromatographic separation is carried out by employing conventional chromatography (e.g., gravity, flash, high pressure (i.e., HPLC) or thin layer chromatography (TLC) ) .
  • conventional chromatography e.g., gravity, flash, high pressure (i.e., HPLC) or thin layer chromatography (TLC)
  • Common materials used are alumina and silica gel as well as other materials known to one skilled in the art.
  • column chromatography with non-ionic resin or by high performance liquid chromatography employing a reverse phase resin may be used.
  • the fractions containing HIV antagonist activity can be assayed by a gpl20/CD4 binding assay described more fully below.
  • more than one chromatographic separation step is employed. In a preferred procedure, one or more separations are carried out employing column chromatography and a final separation is carried out employing preparative thin layer chromatography.
  • silica gel is the preferred adsorbent.
  • silica gel may be used in all the separations, employing different eluting agents.
  • chromatography using silica gel may be combined advantageously with a different adsorbent, e.g., Sephadex LH-20.
  • adsorbents such as alumina, styrene-divinylbenzene copolymers (e.g., HP-20, HP-30, HP-40) and Amberlite
  • XAD-2, XAD-4, XAD-16 may also be employed.
  • a mixture of methanol, methylene chloride, water and formic acid has been found to be especially useful in the fractionation and recovery of the active compounds of the present invention on silica gel (Si ⁇ 2) .
  • the mixture may be employed in isocratic, step gradient or continuous gradient systems. Once isolated, the fractions containing the homogeneous compound(s) may be concentrated under reduced pressure.
  • the purified products can then be analyzed for purity, structure, etc. by such techniques as NMR (e.g., NMR),
  • All the compounds of the present invention are alkaloids of marine origin. Preferably they are polycyclic guanidine alkaloids and derivatives thereof. Such compounds have the general formula:
  • R2 is selected from the group consisting of hydrogen, hydroxy, lower alkyl (C -C4 ) , lower alkenyl(C2 _
  • n is an integer from 1-6.
  • n is 7-9; m is 6-9; and p is 3-5. More preferably, n is 8-9; m is 7-9; and p is . It is further noted that the variables n, m and p are selected independently of each other. - to ⁇
  • R3 is selected from the group consisting of hydrogen, hydroxy, lower alkyl(C . -C4 ) , lower alkenyl(C2-
  • p is an integer from 1-6.
  • q is 6 to 10; r is 1-3; and p is 3-5. More preferably q is 7 to 10; r is 1 or 3; and p is 4.
  • variables q, r and p are selected independently of each other.
  • Aryl refers to phenyl or naphthyl, which may optionally be independently substituted by one or two alkyl(C ⁇ _5), alkoxy(C1-.4) , hydroxy, carboxy, carboalkoxy, carboxamide, phenylalkylene (C1-4) carboxyalkylene(C ⁇ _5) , carboalkoxyalkylene(C ⁇ _5) , carboxamidealkylene(C ⁇ _5) , carboxyalkyloxy(C ⁇ _5) , carboalkoxyalkyloxy(C ⁇ _5) , carboxamidealkyloxy (C1-5) , amino, mono-alkylamino(C]__5) , di-alkylamino(C ⁇ _5) , aminoalkylene(C ⁇ _5) , guanidinyl or guanidinylalkylene(C ⁇ _5) groups.
  • the present invention further encompasses derivatives of compounds of the present invention which comprises chemical modifications known to those skilled in the art.
  • Chemical modifications include, but are not limited to, hydrolysis, esterification, acetylation, and alkylation, which do not destroy the inhibitory function(s) of the present invention.
  • the guanidine residues may be blocked by a condensation reaction with a three-carbon unit.
  • the three-carbon unit may be a ⁇ -dialdehyde, ⁇ -ketoaldehyde, ⁇ -keto ester, malonic ester, or other combinations of these functional groups as further exemplified in the examples section.
  • said derivatives retain the ability to inhibit HIV infectivity at a comparable (i.e., within one log unit) or lower concentration than the unmodified compounds, but with reduced cytotoxicity.
  • Acid addition salts of the compounds of the present invention are prepared in a standard manner in suitable solvents.
  • an excess of an acid such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, or succinic is added to the parent compound, in particular, the acetate salt form is especially usef l.
  • certain of the compounds may form inner salts or zwitterions which may be acceptable.
  • Cationic salts are prepared by treating the parent compound with an excess of an alkylating reagent, such as hydroxide, carbonate or alkoxide containing the appropriate cation. Cations such as Na + , K + , Ca ⁇ + and H + are examples of cations present in pharmaceutically acceptable salts.
  • homologs shall mean compounds with structural formulas that differ from the compounds of the present invention by one or more carbon atoms and one or more pairs of hydrogen atoms.
  • higher homologs of compound V have a C o H 21 or C 11 H 23 side chain in place of the CgH ⁇ g side chain.
  • Isomers include, without limitation, enatiomers, optical isomers and stereoisomers (e.g., cis and trans, + and -, d and 1) .
  • the compounds of the present invention can be assayed for their ability to inhibit HIV infection via binding assays and functional (e.g., fusion or infectivity) assays.
  • One binding assay entails a competition ELISA, measuring the binding inhibition of sT4 to immobilized recombinant gpl20 in the presence and absence of the compounds of the invention.
  • a similar competition RIA entails measuring the binding inhibition of labelled sT4 to (immobilized) recombinant gpl20.
  • Another method entails the inhibition of HIV gpl20 binding to CD4+ cells.
  • Bound gpl20 is detected by gamma counting when using 12 ⁇ -iabelled gpl20 (e.g., by the Bolten-Hunter method) or by flow cytometry when using mouse anti-gpl20 antisera and FITC (fluorescein isothioc anate) labelled goat anti-mouse Ig antisera.
  • FITC fluorescein isothioc anate
  • One functional assay comprises the inhibition of cell fusion between chronically infected cells and uninfected CD4 + cells.
  • HIV infected H9 cells R. Gallo, National Institute of Health, Bethesda, MD, USA
  • uninfected cells at a ratio of 1:2, in the presence of an inhibitory compound.
  • Such assays are performed essentially as described by Sleckman et al., (Nature. 328:351-3 (1987)) and are hereby incorporated by reference.
  • a non-viral syncytium assay can also be used; This assay measures the inhibition of fusion between cells expressing HIV env protein and CD4 + cells as disclosed in U.S. application serial number, 07/587,011, filed September 24, 1990 (Clark et al., "Human Lymphoid Cells Expressing HIV Envelope Protein gpl60”) and incorporated by reference herein.
  • virus infectivity assay comprises infection of T-lymphocytes or macrocyte/macrophages with HIV. At six or more days post-infection measurement of particle-associated reverse transcriptase activity and/or p24 antigen levels can be determined (See, for example, Clapham et al., HalLiX f i, 337: 368-370 (1990) or McDougal et al., J Iirnmin Meth f 2£: 171-183 (1985)).
  • compositions of the compounds of the present invention may be formulated as solutions of lyophilized powders for parenteral administration.
  • Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation is generally a buffered, isotonic, aqueous solution.
  • suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulation is - N - especially suitable for parenteral administration, but may also be used for oral administration. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • the compounds of the present invention may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • Liquid carriers include syrup, peanut oil, olive oil, saline and water.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about lg per dosage unit.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly or filled into a soft gelatin capsule.
  • the dosage ranges for administration of the compounds of the present invention are those to produce the desired effect whereby symptoms of HIV or HIV infection are ameliorated. Effective inhibition may be achieved by using one or a combination of two or more compounds of the present invention. Effective inhibition of HIV is defined as at least one log reduction in the infectivity of free virus preparations.
  • a pharmaceutically effective amount refers to the amount administered so as to maintain an amount which suppresses or inhibits secondary infection by syncytia formation or by circulating virus throughout the period during which HIV infection is evidenced such as by presence of anti-HIV antibodies, presence of culturable virus and presence of p24 antigen in patient sera.
  • the presence of anti-HIV antibodies can be determined through use of standard ELISA or western assays for example, anti-gpl20, anti-gp41, anti-tat, anti-p55, anti-pl7 antibodies, etc.
  • the dosage will generally vary with age, extent of the infection, and counterindications, if any, for example, immune tolerance.
  • the dosage can vary from 0.001 mg/kg/day to 50 mg/kg/day, but preferably 0.01 to 1.0 mg/kg/day.
  • the compounds of the present invention are useful as tools and/or reagents to study protein- protein interactions.
  • the instant compounds selectively inhibit the interaction between HIV and the T-cell surface protein, CD4.
  • the instant compounds are useful as an SAR (structure activity relationships) tool to study, select and/or design other molecules to inhibit HIV.
  • SAR structure activity relationships
  • the sponge Batzella sp. was collected by hand using SCUBA at a depth of 20-30 meters throughout the southern portion of the Berry Islands, Bahamas (ca. 25.5° N, 77.5° W) .
  • a sample of the sponge was deposited in the Zoological Museum of Amsterdam, under a ZMA registry number POR.8788. It was identified by Dr. Rob Van Soest of the Institute of Taxonomic Zoology, University -_b- of Amsterdam, as a new species of the genus Batzella.
  • the freeze-dried sponge (114g) was extracted with EtOAc and eOH-CH2Cl2 (1:1) to give 5.7g and 25.2g extracts respectively.
  • the MeOH-CH2Cl2 extract was then extracted with CH2CI2 to remove excess salt resulting in a dark red/brown residue (6.7g) .
  • 2.1g of the residue was applied to a column of Sephadex® LH-20 and eluted with MeOH:H2 ⁇ (1:1). Fractions (15-20ml) were monitored by UV and pooled.
  • Fractions 110-155 contained active compounds of identical Rf values and appeared homogeneous on Si ⁇ 2TLC using
  • the compounds II-IV represent a novel class of alkaloid natural products.
  • Compound II is an amorphous, colorless, water soluble powder with IR (KBr) bands at 3600-3100 (N-H & O-H) , 3100-2800 (C-H) , 1733 (ester), 1696 and 1684
  • the UV spectrum is very similar to that of I and has ⁇ max 205 ( ⁇ 20098) and 288 nm ( ⁇ 6824) .
  • the FABMS of II displays a molecular ion at 768 (M+H) and corresponds to the molecular formula C42H74N9O4 by HRFABMS.
  • the FABMS also shows two more peaks at m/z 754 and 740 attributable to the molecular ions of lower homologs of II.
  • the FABMS displayed a molecular ion at 738 (M+H) which corresponded to the molecular formula C ⁇ Hg8 N 9 0 in its HRFABMS.
  • the FABMS also showed peaks at m/z 724 and two further molecular ions at m/z 752 & 766 attributable to higher homologs of compound III.
  • This white, amorphous, inactive and highly toxic metabolite had IR and UV spectral properties similar to those of I. It showed peaks at 3600-3100, 3100-2800, 1701, 1688, 1652, 1219 and 1092 cm “1 in IR spectrum and had UV (MeOH) ⁇ max at 206 and 287 nm.
  • the FABMS which shows a molecular ion at 489 (M+H) also had peaks at m/z 503 and 517, due to the higher homologs of V.
  • An intense ion at m/z 114 similar to all other compounds suggested the presence of same n-butyl guanido ester moiety.
  • Compound III was also modified using 1,2- cyclohexanedione (see structure A) . Both modified compounds II and HI were active in an Elisa assay and showed reduced cytotoxicity relative to the unmodified compounds.
  • Table 1 summarizes eleven compounds tested for activity in a CD4 gpl20 binding assay and the IC50 cytotoxicity values.
  • gpl20 In the ELISA assay, goat anti-mouse antibody was coated onto microtiter plates which in turn immobilizes a monoclonal antibody to HIV gpl20. gpl20 is then captured onto the plates and appropriate concentrations of compounds of the present invention are applied followed by the addition of soluble CD4. The bound CD4 is then quantitated by treatment with HRP-conjugated rabbit anti-CD4. In the Whole cell binding assay, gpl20 is incubated with the compound(s) of the present invention for 30 minutes followed by the addition of CD4 + T cells for 30 minutes. The cell associated gpl20 is then detected by treatment with a monoclonal antibody to gpl20 followed by FITC-conjugated goat anti-mouse antibody. The analysis is then performed by flow cytometry.
  • Cytotoxicity was tested with the CD4 + cell line, SupTl (J. Hoxie, Univ. of Pennsylvania, Philadelphia, PA, USA) (see also, Sattentau et al., J Exp Med, 170:1319-1334 (1989)).
  • the compounds of the present invention were dissolved in DMSO in order to maximize solubility and provide a common solvent system.
  • the final concentration of DMSO in the cytotoxicity assay did not exceed 2% of the total volume. Cytotoxicity was measured as the inhibition of H-thymidine incorporation into the host cell's genome after exposure to the compounds of the present invention.
  • cell viability can be measured 18-20 hours after exposure to the compounds of the present invention by measuring the reductive capacity (e.g., MTT [3-(4,5-dimethylthiazol-2- yl)-2,5 diphenyl tetrazolium bromide] or XTT reagents), and thereby indirectly measure cell viability, of cells in a microtiter format.
  • reductive capacity e.g., MTT [3-(4,5-dimethylthiazol-2- yl)-2,5 diphenyl tetrazolium bromide] or XTT reagents
  • Other cell lines that are available to one skilled in the art include CEM, MOLT 4, AA5, MT-2 and H9 (see, Jacobs, J Na l Cancer Inst r .21:231 (1965) ) .
  • Table 2 summarizes the results of a syncytial assay, i.e., the ability of compounds to inhibit HIV- induced fusion of CD4 positive T-cell lines.
  • the syncytial assay is performed essentially as follows.
  • test compounds were assessed for their ability to inhibit the HIV-induced fusion of CD4 positive T-cell lines.
  • Serial 2 fold dilutions of standard positive control sT4 (soluble T4 or CD4) or test Batzella compound were made in RPMI 1640 containing 10% fbs and 20 ⁇ l of each dilution were added to duplicate wells of half-area 96 well tissue culture plates (COSTAR) .
  • Cells from a CEM cell line persistently infected with HIVTUB anc 9 r o wn ⁇ n RPMI 1640 containing
  • the compounds of the present invention can be assayed in a virus neutralization assay (or HIV infectivity assay) as follows.
  • inhibitor i.e., purified compound, natural product extract, etc.
  • Alternative infectivity Assays can be set up by infecting cells in bulk for 1 hr, washing cells to remove unabsorbed virus, then adding 100 ⁇ l (3 x lO ⁇ /ml) of infected cells per well. Dilutions of inhibitors are then added to the infected cell cultures at 0 hr post infection.

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Abstract

L'invention concerne de nouveaux composés marins et leurs dérivés inhibant l'infection par le VIH-1.
PCT/US1992/005517 1991-07-09 1992-06-30 Composes marins (alcaloides) utiles comme inhibiteurs du vih WO1993001193A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU777578B2 (en) * 1999-06-30 2004-10-21 Regents Of The University Of California, The Hexahydropyrrolo(1,2-C)pyrimidines as antiviral, antifungal and/or antitumor agents
CN113943298A (zh) * 2021-10-14 2022-01-18 中国人民解放军军事科学院防化研究院 一种胍胺类天然产物Crambescin A的合成方法

Citations (2)

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US4959370A (en) * 1989-03-29 1990-09-25 Phillip Crews Alkaloids of marine origin
US5028613A (en) * 1990-02-16 1991-07-02 Repligen Corporation Novel pyrroloquinoline alkaloids and methods of use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4959370A (en) * 1989-03-29 1990-09-25 Phillip Crews Alkaloids of marine origin
US5028613A (en) * 1990-02-16 1991-07-02 Repligen Corporation Novel pyrroloquinoline alkaloids and methods of use

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Title
JOURNAL OF AMERICAN CHEMICAL SOCIETY, 1989, KASHMAN et al., "Ptilomycalin A: A Novel Polycyclic Guanidine Alkaloid of Marine Origin", pp. 8925-8926. *
JOURNAL OF ORGANIC CHEMISTRY, 13 September 1991, JARES-ERIJMAN et al., "Crambesidins: New Antiviral and Cytotoxic Comounds from the Sponge Crambe Crambe", pp. 5712-5715. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU777578B2 (en) * 1999-06-30 2004-10-21 Regents Of The University Of California, The Hexahydropyrrolo(1,2-C)pyrimidines as antiviral, antifungal and/or antitumor agents
CN113943298A (zh) * 2021-10-14 2022-01-18 中国人民解放军军事科学院防化研究院 一种胍胺类天然产物Crambescin A的合成方法

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