- Structural requirements for antileukemic activity among the naturally occurring and semisynthetic maytansinoids.
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In an effort to determine the structural requirements for the significant antileukemic, cytotoxic, antitubulin, and antimitotic activity exhibited by the novel ansa macrolide, maytansine (1), four new C-3 ester and six new C-9 ether homologues were synthesized. The biological activities of these compounds were assayed and compared to the activities of previously reported, naturally occurring maytansinoids. From the data, it is apparent that presence of the C-3 ester is necessary for significant activity, and variations in the ester group are not accompanied by marked changes in activity. However, elimination of the ester group, as in maytansinol (7), maysine (8), normaysine (9), and maysenine (10), results in a significant decrease in biological activity. Blockage of the C-9 carbinolamide via etherification markedly reduces antileukemic and cytotoxic activity and slightly reduces antitubulin activity but has relatively little effect on antimitotic activity against sea urchin eggs. Thus, a free carbinolamide at C-9 is advantageous for optimal activity.
- Kupchan,Sneden,Branfman,Howie,Rebhun,McIvor,Wang,Schnaitman
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- A highly potent maytansinoid analogue and its use as a cytotoxic therapeutic agent in gold nanoparticles for the treatment of hepatocellular carcinoma
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Gold nanoparticles are promising drug delivery agents with the potential to deliver chemotherapeutic agents to tumour sites. The highly cytotoxic maytansinoid tubulin inhibitor DM1 has been attached to gold nanoparticles and shows tumour growth inhibition in mouse models of hepatocellular carcinoma. Attempting to improve the stability of the gold-cytotoxin bond led to the design and synthesis of novel maytansinoids with improved potency in cell viability assays and improved in vivo tolerability compared to the DM1 analogues. These novel maytansines may also have applications in other methods of drug delivery, for example as the cytotoxic component of antibody drug conjugates.
- Porter, John,Ding, Yao,Hale, Sarah J.M.,Perrins, Richard D.,Robinson, Angela,Mazanetz, Michael P.,Wu, Yubo,Ma, Yinping,Conlon, Kelly,Coulter, Tom
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Read Online
- Maytansine dechloridation compound, intermediate, preparation method of compound and application
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The invention discloses a maytansine dechloridation compound as shown in a formula I, an intermediate, a preparation method of the compound and an application. The invention provides the maytansine dechloridation compound as shown in the formula I. The maytansine dechloridation compound can be used as an impurity standard substance for impurity research of maytansine DM1 to establish an analysis method for maytansine DM1 quality control, and a proper method is selected to effectively remove the impurities. The quality of maytansine DM1 and even ADC drugs and the safety and effectiveness of clinical application can be improved. The invention also provides the preparation method and the intermediate of the maytansine dechloridation compound as shown in the formula I.
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Paragraph 0074-0077
(2020/12/09)
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- Uses of immunoconjugates targeting CD138
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Disclosed is a method and composition for treating a disease associated with target cells expressing CD138 in a multiple dose regimen. An immunoconjugate comprising an engineered targeting antibody targeting CD138 expressing cells and an effector molecule is administered in a multiple dose regimen. The multiple dose regimen comprises at least two doses and the aggregate dose administered within an active treatment cycle is an aggregate maximum tolerable dose (AMTD) or a fraction of the AMTD. The AMTD and/or said fraction exceeds the dose resulting in dose limiting toxicity (DLT) and/or exceeds the maximum tolerable dose (MTD) when the immunoconjugate is administered as a single dose, including as part of a multiple single dose regimen within said active treatment cycle.
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Page/Page column 12
(2018/11/23)
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- Uses of immunoconjugates targeting CD138
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Disclosed are methods and treatment regimes that include the administration of immunconjugates targeting CD138 to combat diseases. The immunoconjugate is either used as the sole active ingredient, as part of a treatment regime or as part of an anticancer combination.
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- MAYTANSINOID ANALOGS AS ANTITUMOR AGENTS
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Ansamycin analogs, including maytansinoid analogs, and their use in treating cell proliferative diseases and conditions, and in particular, for use as antitumor agents.
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Page/Page column 9
(2008/06/13)
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- Process for preapring maytansinol
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Processes for preparing maytansinol from disulfide-containing maytansinoid esters by reduction with LiAlH4. The maytansinol is useful for preparing cell-binding agent/maytansinoid complexes.
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Page/Page column 3
(2008/06/13)
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- Total synthesis of (-)-maytansinol
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A total synthesis of maytansinol (1) was achieved, in a convergent way, using (3S,6S,7S)-aldehyde 4 and (S)-p-tolyl sulfoxide 3 as fragments. When the anion of 3 was condensed with aldehyde 4, some induction at C(10) was observed (60% de), giving the C(1)-N(19)-open-chain compound 7, after thermal elimination of sulfinate. Pure E/E stereochemistry of the 11,13-diene was obtained. Selective modifications of the functionalities permitted macrocyclization and further elaboration to maytansinol.
- Benechie, Michel,Khuong-Huu, Francoise
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p. 7133 - 7138
(2007/10/03)
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