- Linker, linker-containing antibody conjugate drug and application of linker
-
The invention relates to a linker as shown in a formula I, a linker-containing antibody conjugate drug and an application of the linker, also relates to a pharmaceutical composition comprising the antibody conjugate drug, and also relates to an application of the antibody conjugate drug to the treatment and/or prevention of diseases.
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Paragraph 0171-0173; 0183-0186
(2020/02/20)
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- CONJUGATION LINKERS CONTAINING 2,3-DIAMINOSUCCINYL GROUP
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Provided is a conjugate of a cytotoxic drug/molecule to a cell-binding molecule with a bis-linker (adual-linker) containing a 2, 3-diaminosuccinyl group. It also relates to preparation of the conjugate of a cytotoxic drug/molecule to a cell-binding molecule with the bis-linker, particularly when the drug having functional groups of amino, hydroxyl, diamino, amino-hydroxyl, dihydroxyl, carboxyl, hydrazine, aldehyde and thiol for conjugation with the bis-linker in a specific manner, as well as the therapeutic use of the conjugates.
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Page/Page column 180
(2020/05/19)
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- Anisotropic dynamics and mechanics of macromolecular crystals containing lattice-patterned polymer networks
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The mechanical and functional properties of many crystalline materials depend on cooperative changes in lattice arrangements in response to external perturbations. However, the flexibility and adaptiveness of crystalline materials are limited. Additionally, the bottom-up, molecular-level design of crystals with desired dynamic and mechanical properties at the macroscopic level remains a considerable challenge. To address these challenges, we had previously integrated mesoporous, cubic ferritin crystals with hydrogel networks, resulting in hybrid materials (polymer-integrated crystals or PIX) which could undergo dramatic structural changes while maintaining crystalline periodicity and display efficient self-healing. The dynamics and mechanics of these ferritin-PIX were devoid of directionality, which is an important attribute of many molecular and macroscopic materials/devices. In this study, we report that such directionality can be achieved through the use of ferritin crystals with anisotropic symmetries (rhombohedral or trigonal), which enable the templated formation of patterned hydrogel networks in crystallo. The resulting PIX expand and contract anisotropically without losing crystallinity, undergo prompt bending motions in response to stimuli, and self-heal efficiently, capturing some of the essential features of sophisticated biological devices like skeletal muscles.
- Han, Kenneth,Bailey, Jake B.,Zhang, Ling,Tezcan, F. Akif
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supporting information
p. 19402 - 19410
(2020/11/13)
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- A CONJUGATE OF A TUBULYSIN ANALOG WITH BRANCHED LINKERS
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The present invention relates to the conjugation of a tubulysin analog compound to a cell-binding molecule with branched/side-chain linkers for having better delivery of the conjugate compound and targeted treatment of abnormal cells. It also relates to a branched-linkage method of conjugation of a tubulysin analog molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and autoimmune disease.
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Paragraph 000422; 000423
(2021/03/02)
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- Poly[(side-on mesogen)-Alt-(end-on mesogen)]: A compromised molecular arrangement
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In recent years, sequence-controlled side-chain liquid crystal polymers (SCLCPs) have gained extensive interest because mesogenic units with different lengths and distributions can form various ordered sequences, which further endow LCP materials with diverse functions. In this manuscript, a side-chain side-on maleimide-containing monomer 2,5-bis-(4-butoxy-benzoyloxy)-benzoic acid 6-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-hexyl ester (Y1801) and a side-chain end-on styrene-containing monomer 4′-[6-(4-vinyl-phenoxy)-hexyloxy]-biphenyl-4-carbonitrile (Y1802) are combined in one single macromolecular chain and orderly polymerized in an alternative sequence to form an alternating copolymer Poly(Y1801-Alt-Y1802). The chemical structure and alternating sequence of Poly(Y1801-Alt-Y1802) are confirmed by GPC and NMR techniques. The combination of DSC, POM, and WAXS data indicates that, although the side-on homopolymer PY1801 and the end-on homopolymer PY1802 both exhibit the nematic phase, their alternating copolymer Poly(Y1801-Alt-Y1802) shows an interdigitated smectic A phase, a compromised molecular arrangement instead. In addition, a strong fluorescence emission of Poly(Y1801-Alt-Y1802) is observed, which might provide this novel alternating-structured liquid crystal polymer with potential applications in luminescent materials and devices.
- Wang, Meng,Bao, Wei-Wei,Chang, Wen-Ying,Chen, Xu-Man,Lin, Bao-Ping,Yang, Hong,Chen, Er-Qiang
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p. 5791 - 5800
(2019/08/26)
-
- A CONJUGATE OF A TUBULYSIN ANALOG WITH BRANCHED LINKERS
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The present invention relates to the conjugation of a tubulysin analog compound to a cell-binding molecule with branched/side-chain linkers for having better delivery of the conjugate compound and targeted treatment of abnormal cells. It also relates to a branched-linkage method of conjugation of a tubulysin analog molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and autoimmune disease.
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Page/Page column 12; 189
(2019/07/17)
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- NOVEL HYDROPHILIC LINKERS AND LIGAND-DRUG CONJUGATES THEREOF
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Hydrophilic linkers are useful for linking drugs to cell-binding ligands in ligand-drug conjugates, such as antibody-drug conjugates. The ligand-drug conjugate includes a cell-binding ligand capable of binding to a particular cell population, and a drug connected to the ligand by a hydrophilic linker. The hydrophilic linker includes one or more hydrophilic groups that render the linker hydrophilic. The hydrophilic linker may also include functional groups at the two termini for coupling to the drug and the cell-binding ligand respectively.
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Paragraph 0158-0159
(2019/05/15)
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- Novel silyl ether-based acid-cleavable antibody-MMAE conjugates with appropriate stability and efficacy
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Antibody-drug conjugate (ADC) is a novel efficient drug delivery system that has been successfully used in clinical practice, and it has become a research hotspot in the anti-tumor drug field. Acid-cleavable linkers were first used in clinical ADCs, but their structural variety (e.g., hydrazone and carbonate) is still limited, and their stability is usually insufficient. Designing novel acid-cleavable linkers for the conjugation of the popular cytotoxin monomethyl auristatin E (MMAE) has always been a significant topic. In this paper, we generate a novel, silyl ether-based acid-cleavable antibody-MMAE conjugate, which skillfully achieves efficient combination of amino-conjugated MMAE with the acid-triggered silyl ether group by introducing p-hydroxybenzyl alcohol (PHB). The stability, acid-dependence cleavage, effective mechanism, efficacy and safety of the resulting ADC were systematically studied; the results show that it exhibits a significant improvement in stability, while maintaining appropriate efficacy and controlled therapeutic toxicity. This strategy is expected to expand a new type of acid-cleavable linkers for the development of ADCs with highly potent payloads.
- Wang, Yanming,Fan, Shiyong,Xiao, Dian,Xie, Fei,Li, Wei,Zhong, Wu,Zhou, Xinbo
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-
- Catalytic Asymmetric [4+2]-Cycloadditions Using Tropolones: Developments, Scope, Transformations, and Bioactivity
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An organocatalyzed asymmetric [4+2]-cycloaddition between tropolones and electron-deficient dienophiles is presented. Complex and biologically interesting dihydrohomobarrelenone scaffolds are formed through a Diels–Alder reaction utilizing bifunctional Br?nsted-base catalysis, affording the corresponding bridged bicyclic cycloadducts in up to quantitative yields with good enantio- (up to 92 % ee) and diastereoselectivity (up to >20:1 d.r.). The synthetic value of the obtained products is explored by downstream transformations, including photoisomerizations, and their biological relevancy by in vivo testing in MCF-7 cancer cells.
- Hammer, Niels,Erickson, Jeremy D.,Lauridsen, Vibeke H.,Jakobsen, Joakim B.,Hansen, Bente K.,Jacobsen, Kristian M.,Poulsen, Thomas B.,J?rgensen, Karl Anker
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supporting information
p. 13216 - 13220
(2018/09/25)
-
- TARGETED PEPTIDE CONJUGATES
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The present invention relates to the preparation and use of therapeutic compounds for the treatment of diseases at specific subcellular target areas such as specific cellular organelles. In particular, the therapeutic compounds of the invention are specific for modifying enzyme activity within targeted organelles or structures of cells and tissues. Subcellular organelles and structures that may be specifically targeted by compounds of the present invention include lysosomes, autophagasomes, the endoplasmic reticulum, the Golgi complex, peroxisomes, the nucleus, membranes and the mitochondria.
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-
Paragraph 0159; 0269; 0270
(2018/08/12)
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- Striking a Balance between Carbonate/Carbamate Linkage Bond- and Reduction-Sensitive Disulfide Bond-Bearing Linker for Tailored Controlled Release: In Situ Covalent-Albumin-Binding Gemcitabine Prodrugs Promote Bioavailability and Tumor Accumulation
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To address the challenges of rapid enzyme inactivation, poor tumor targeting, and acquired drug resistance in gemcitabine (GEM) application, we report two groups of maleimide-functionalized GEM prodrugs conjugating covalently in situ with Cys-34 of blood-circulating albumin and then resulting in macromolecular prodrugs after intravenous administration. Tailored and accurate controlled release was achieved through different combinations of linkage bonds, relatively stable and labile (carbamate and carbonate, respectively), and linkers with or without insertion of a disulfide bond. Interestingly, we found that the overall advantages or disadvantages brought by a disulfide bond varied with the stability of the linkage bond. Finally, the carbonate linkage bond-bearing group, especially the one with a linker lacking a disulfide bond, stood out with remarkably increased bioavailability (21-fold greater than GEM) and efficient tumor free-GEM accumulation (8-fold of GEM), which consequently contributed to excellent in vivo antitumor efficacy.
- Zhang, Huicong,Wang, Kuanglei,Na, Kexin,Li, Dan,Li, Zhenbao,Zhao, Dongyang,Zhong, Lu,Wang, Menglin,Kou, Longfa,Luo, Cong,Zhang, Haotian,Kan, Qiming,Ding, Huaiwei,He, Zhonggui,Sun, Jin
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p. 4904 - 4917
(2018/05/29)
-
- DERIVATIVES OF AMANITA TOXINS AND THEIR CONJUGATION TO A CELL BINDING MOLECULE
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Derivatives of Amernita toxins of Formula (I), wherein, formula (a) R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X, L, m, n and Q are defined herein. The preparation of the derivatives. The therapeutic use of the derivatives in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.
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Page/Page column 149; 150
(2017/04/11)
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- RADIOPHARMACEUTICAL CONJUGATE
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This invention relates new radiopharmaceutical conjugates for use in improved methods of diagnosis and treatment of cancer. The radiopharmaceutical conjugate comprises, in sequence: a metabolite that targets tumour cells, bound to a chelating agent capable of containing a radionuclide.bound to a linker capable of binding with an EPR agent in vitro or in vivo; or a chelating agent capable of containing a radionuclide, bound to a metabolite that targets tumour cells, bound to a linker capable of binding with an EPR agent in vitro or in vivo. The radiopharmaceutical conjugates of the present invention provide active and passive targeted radionuclide delivery systems that can help to improve the biodistribution and pharmacological toxicity of the radiopharmaceuticals used for the diagnosis and therapy of cancer.
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Page/Page column 55-56
(2016/04/20)
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- Indium-Catalyzed Amide Allylation of N-Carbonyl Imides: Formation of Azaspiro-γ-lactones via Ring Opening-Reclosure
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A novel and facile synthesis of azaspiro-γ-lactones with a methylene-lactam framework from N-carbonyl imides is described. Mechanistic investigations provide evidence for a two-step reaction process involving ZnCl2-promoted addition of β-amido allylindium species followed by an unexpectedly molecular-sieves-mediated ring opening-reclosure concomitantly with the loss of an N-carbonyl unit.
- Sengoku, Tetsuya,Murata, Yusuke,Aso, Yuwa,Kawakami, Ai,Inuzuka, Toshiyasu,Sakamoto, Masami,Takahashi, Masaki,Yoda, Hidemi
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supporting information
p. 5846 - 5849
(2015/12/11)
-
- Preparation of asymmetric urea derivatives that target prostate-specific membrane antigen for SPECT imaging
-
Prostate-specific membrane antigen (PSMA) has been identified as a diagnostic and therapeutic target for prostate cancer. (S)-2-[3-[(R)-1-Carboxy- 2-mercaptoethyl]ureido-pentanedioic acid (Cys-CO-Glu) were used to design novel PSMA targeting probes by nucleophilic conjugate addition between cysteine and maleimide based reagents. 3 ([123I]IGLCE) was synthesized by this strategy and showed high affinity for PSMA. Results of binding inhibition assays of these derivatives suggested the importance of an aromatic group and succinimide moiety for high affinity. [123I]3 was evaluated in vivo with PSMA positive LNCaP and PSMA negative PC-3 human prostate cancer xenograft bearing mice. [125I]3 accumulated in LNCaP tumors but not in PC-3 tumors, and the accumulation was inhibited by 2-(phosphonomethyl)pentanedioic acid (2-PMPA). Use of [123I]3 provided positive images of LNCaP tumors in single photon emission tomography scans. These results warrant further evaluation of [123I]3 and its derivatives as radiolabeled probes for the diagnosis of prostate cancer.
- Harada, Naoya,Kimura, Hiroyuki,Ono, Masahiro,Saji, Hideo
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p. 7890 - 7901
(2013/11/06)
-
- Synthesis and characterization of fluorinated conjugates of albumin
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A small fluorocarbon dendron that contains nine chemically identical fluorine atoms was covalently conjugated to albumin via a flexible linker. Two versions were made, which differ by 10% in the linker length. Both versions display split 19F signal and much shorter 19F longitudinal relaxation time than their small molecule counterparts. 10% difference in the flexible linker length has negligible impact on the 19F signal.
- Yue, Xuyi,Feng, Yue,Yu, Y. Bruce
-
supporting information
p. 173 - 181
(2013/11/06)
-
- Synthesis of a bridging ligand with a non-denatured protein pendant: Toward protein encapsulation in a coordination cage
-
Toward protein encapsulation by a synthetic host, we synthesized an ubiquitin-dangled ligand, a potential precursor of a nanoscale coordination cage. The key step is the addition of a C-terminal Cys76 SH group, which was introduced by Gly76Cys mutation, to a maleimide acceptor on the ligand. The C-terminal mutation and the SH addition to the ligand did not damage the ubiquitin moiety at all, neither structurally nor conformationally.
- Fujita, Daishi,Suzuki, Kosuke,Sato, Sota,Yagi-Utsumi, Maho,Kurimoto, Eiji,Yamaguchi, Yoshiki,Kato, Koichi,Fujita, Makoto
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supporting information; scheme or table
p. 313 - 315
(2012/06/01)
-
- Functionalized phosphonated half-cage molecules as ligands for metal complexes
-
Phosphonated molecules, featuring a half-cage structure and a N-lateral chain with additional metal coordinating groups were designed as ligands of metal cations. These compounds were synthesized by a Diels-Alder (DA) strategy, using 1-diethoxyphosphoryl-1,3-butadiene and a series of N-substituted maleimides as dienophiles. Two cycloadducts, bearing a terminal primary alcohol and a terminal iodide, respectively, were used as key intermediates for further functionalizations. Metal coordination properties of the ligands equipped with functionalized N-lateral chains were proven by an ESI-HRMS study. The stoichiometry of one selected EuIII complex with a diphosphonated ligand was determined by photoluminescence spectroscopy in emission mode.
- Villemin, Elise,Herent, Marie-France,Marchand-Brynaert, Jacqueline
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supporting information
p. 6165 - 6178
(2013/01/15)
-
- A two-directional strategy for the diversity-oriented synthesis of macrocyclic scaffolds
-
Macrocyclic compounds represent a structural class with exceptional potential for biological activity; however, they have historically been underrepresented in screening collections and synthetic libraries. In this article we report the development of a highly step-efficient strategy for the diversity-oriented synthesis of complex macrocyclic architectures, using a modular approach based on the two-directional synthesis of bifunctional linear precursors and their subsequent combination in a two-directional macrocyclisation process. In this proof of principle study, the synthesis of 14 such compounds was achieved. Cheminformatic analysis of the compounds produced suggests that they reside in biologically relevant regions of chemical space and the compounds were screened for activity against two cancer cell lines.
- O'Connell, Kieron M. G.,Beckmann, Henning S. G.,Laraia, Luca,Horsley, Helen T.,Bender, Andreas,Venkitaraman, Ashok R.,Spring, David R.
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supporting information
p. 7545 - 7551
(2012/10/29)
-
- Preparation of FRET reporters to support chemical probe development
-
In high throughput screening (HTS) campaigns, the quality and cost of commercial reagents suitable for pilot studies often create obstacles upon scale-up to a full screen. We faced such challenges in our efforts to implement an HTS for inhibitors of the phosphopantetheinyl transferase Sfp using an assay that had been validated using commercially available reagents. Here we demonstrate a facile route to the synthetic preparation of reactive tetraethylrhodamine and quencher probes, and their application to economically produce fluorescent and quencher-modified substrates. These probes were prepared on a scale that would allow a full, quantitative HTS of more than 350,000 compounds.
- Foley, Timothy L.,Yasgar, Adam,Garcia, Christopher J.,Jadhav, Ajit,Simeonov, Anton,Burkart, Michael D.
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experimental part
p. 4601 - 4606
(2010/11/18)
-
- TARGETED POLYMERIC PRODRUGS CONTAINING MULTIFUNCTIONAL LINKERS
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The present invention provides single chain antibody-directed polymeric prodrugs containing multifunctional linkers. Methods of making the polymeric delivery systems and methods of treating mammals using the same are also disclosed.
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- Two-step labeling of endogenous enzymatic activities by Diels-Alder ligation
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A ligation strategy based on the Diels-Alder [4+2] cycloaddition for the two-step activity-based labeling of endogenously expressed enzymes in complex biological samples has been developed. A panel of four diene-derivatized proteasome probes was synthesized, along with a dienophile-functionalized BODIPY(TMR) tag. These probes were applied in a Diels-Alder labeling procedure that enabled us to label active proteasome β-subunits selectively in cellular extracts and in living cells. We were also able to label the activity of cysteine proteases in cell extracts by utilizing a diene-derivatized cathepsin probe. Importantly, the Diels-Alder strategy described here is fully orthogonal with respect to the Staudinger-Bertozzi ligation, as demonstrated by the independent labeling of different proteolytic activities by the two methods in a single experiment.
- Willems, Lianne I.,Verdoes, Martijn,Florea, Bogdan I.,Van Der Marel, Gijsbert A.,Overkleeft, Herman S.
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experimental part
p. 1769 - 1781
(2011/04/18)
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- Development of polymeric phase change materials on the basis of diels-alder chemistry
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Diels-Alder (DA) chemistry is increasing popular due to its simplicity and efficiency; however, one concept that has yet to be thoroughly explored is incorporation of DA linkages within materials for the development of polymeric phase change materials. It is well established that the retro-DA reaction results in a large endotherm, which could be a potential energy sink for phase change materials. Hydroxyl-terminated polybutadiene (HTPB) was selected as a prepolymer and modified with different DA linkages. Cured materials were prepared upon addition of diisocyanates and their physical properties of the cured elastomers were investigated using thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and rheological testing. The resulting thermally responsive HTPB (TR-HTPB) exhibited the ability to absorb energy and flow at elevated temperatures. Furthermore, they displayed unusual responses to repeated thermal cycling, including changes in thermal absorption and rheological characteristics.
- Swanson, John P.,Rozvadovsky, Svetlana,Seppala, Jonathan E.,MacKay, Michael E.,Jensen, Robert E.,Costanzo, Philip J.
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scheme or table
p. 6135 - 6141
(2011/11/12)
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- Temperature-regulated activity of responsive polymer-protein conjugates prepared by grafting-from via RAFT polymerization
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A facile route to well-defined "smart" polymer-protein conjugates with tunable bioactivity is reported. Protein modification with a reversible addition-fragmentation chain transfer (RAFT) agent and subsequent room temperature polymerization in aqueous media led to conjugates of poly(N-isopropylacrylamide) and a model protein. Representing the first example of polymer-protein conjugation with RAFT agent immobilization via the "R-group" approach, high molecular weight and reductively stable conjugates were accessible without extensive purification or adverse effects on the protein structure. An increase in molecular weight with conversion was observed for the chains grafted from the protein surface, confirming the controlled nature of the polymerization. The responsive behavior of the immobilized polymer facilitated conjugate isolation and also allowed environmental modulation of bioactivity. Copyright
- De, Priyadarsi,Li, Ming,Gondi, Sudershan R.,Sumerlin, Brent S.
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supporting information; experimental part
p. 11288 - 11289
(2009/02/05)
-
- TARGETED POLYMERIC PRODRUGS CONTAINING MULTIFUNCTIONAL LINKERS
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The present invention provides single chain antibody-directed polymeric prodrugs containing multifunctional linkers. Methods of making the polymeric delivery systems and methods of treating mammals using the same are also disclosed.
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Page/Page column 70
(2008/06/13)
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- Method for producing water-soluble saccharide conjugates and saccharide mimetics by diels-alder reaction
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The present invention relates to a method by which saccharide compounds can be prepared in a very easy way. This method comprises the steps of: (a) attaching at least one saccharide to a cyclic or acyclic diene, (b) reacting the saccharide-containing diene obtained in step (a) or a commercially available saccharide-containing diene with a dienophile by Diels-Alder reaction.
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- A novel radioiodination reagent for protein radiopharmaceuticals with L- lysine as a plasma-stable metabolizable linkage to liberate m-iodohippuric acid after lysosomal proteolysis
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Radiochemical design of polypeptides using metabolizable linkages would be attractive to enhance target-selective localization of radioactivity for diagnostic and therapeutic nuclear medicine. However, while use of ester bonds as the linkage allows selective release of the designed radiometabolite from covalently conjugated polypeptide after lysosomal proteolysis in nontarget tissues, low plasma stability of ester bonds causes a decrease in radioactivity levels of the target. In pursuit of new metabolizable linkages that provide stable attachment of radiolabels with polypeptide in plasma while facilitating rapid and selective release of designed radiometabolites of rapid urinary excretion in lysosomes, a new radioiodination reagent with L-lysine as the metabolizable linkage to liberate m-iodohippuric acid (L- HML) was designed and synthesized. Stabilities of the metabolizable linkage in serum and cleavabilities of the linkage in lysosomal proteloysis in hepatic cells were investigated after conjugation of [131I]-L-HML iwht galactosyl-neoglycoalbumin (NGA). For comparison, a radioiodination reagent with an ester bond to release m-iodohippuric acid (MIH) was conjugated with NGA under similar conditions. When incubated in human serum, [131I-L-HML- NGA liberated less than 3% of the initial radioactivity after 24 h, whereas [125I]MIH-NGA released more than 60% of its radioactivity during the same interval. In biodistribution studies, [131I]-L-HML-NGA demonstrated radioactivity elimination from murien liver at a rate and excretion route similar to [125I]MIH-NGA. Analyses of murine urine after injection of [131I]-L-HML-NGA indicated a single radioactivity peak at fractions identical to those of m-iodohippuric acid. Biodistribution studies of radioiodinated NGAs with D-lysine or cadaverine as the linkages demonstrated a delayed elimination rate from murine liver with significantly higher radioactivity being excreted in the feces at 24 h postinjection. Thus, L-HML is the first reagent that allows stable attachment of radiolabel with polypeptide in serum while facilitating selective release of a radiometabolite with rapid urinary excretion from covalently conjugated polypeptides after lysosomal proteolysis at a rate similar to that of ester bonds. Thus, L-HML is potentially useful for the radioiodination of polypeptides for diagnostic and therapeutic purposes.
- Wakisaka, Kouji,Arano, Yasushi,Uezono, Takashi,Akizawa, Hiromichi,Ono, Masahiro,Kawai, Keiichi,Ohomomo, Yoshiro,Nakayama, Morio,Saji, Hideo
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p. 2643 - 2652
(2007/10/03)
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- Tris-maleimido compounds as intermediates in trifunctional antibody synthesis
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The present invention is directed to a compound for use as an intermediate in the production of novel trifunctional antibody-like compounds. More particularly, the present invention is directed to a compound of the formula: STR1 wherein X is STR2 wherein k=1 or 0; wherein Z is STR3 wherein s=1 or 0; wherein n=1 or 0; wherein q=1 or 0; wherein Y is STR4 wherein Y', is STR5 wherein p or m may be the same or different and are integers ranging from 0 to 20 with the proviso that when n=0, the sum of m and p is an integer ranging from 1 to 20, whereas when n=1, p and m are each an integer that is at least 1 and the sum of p and m is an integer ranging from 2 to 20; wherein R1 is straight or branched chain lower alkyl having from 1 to 6 carbon atoms or lower alkoxy having from 1-6 carbon atoms; and wherein R2 is hydrogen, phenyl, --COOH, or straight or branched chain lower alkyl having from 1-6 carbon atoms, with the proviso that the lower alkyl moiety may be mono substituted by --NH2, --OH, or --COOH. The compound of the present invention is useful as a trivalent coupling agent for linking Fab'-like fragments to form both bifunctional and trifunctional antibody-like compounds.
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- New conjugates of vinblastine and its derivatives, process for preparing them and pharmaceutical compositions containing them
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A description is given of conjugates of vinca alkaloid of the indole-dihydroindole type with a protein or a protein fragment, corresponding to the general formula STR1 in which R1 denotes a protein or a protein fragment; R2 is COO(C1-3 alkyl) or CO--R7 where R7 is NH2 or an amino acid ester or peptide ester; R3 is H, CH3 or CHO; when R5 and R6 are taken separately, R6 is H and one of R4 and R5 is ethyl and the other is H or OH; when R5 and R6 are taken together with the carbon atoms to which they are attached, they form an oxirane ring and R4 is ethyl, and A is a residue of a bifunctional organic derivative of the maleoylamino acid or maleoyl peptide or maleoylphenoxy type.
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