57103-68-1

Basic information

• Product Name: Maytansine, O3-de2-(acetylmethylamino)-1-oxopropyl-
• Synonyms: Maytansine, O3-de2-(acetylmethylamino)-1-oxopropyl-;MAYTANSINOL;3-O-De[2-[methyl(acetyl)amino]-1-oxopropyl]maytansine;Maytansine,3-O-de[2-;3-o-de(2-(acetylMethylaMino)-1-oxopropyl)Maytansine;ansaMitocin p 0;antibiotic c 15003p;Maytansine,3-O-de[2-(acetylMethylaMino)-1-oxopropyl]-
• CAS NO: 57103-68-1
• Molecular Formula: C₂₈H₃₇ClN₂O₈
• Molecular Weight: 565.05
• Product Categories: Anti-cancerIntermediates & Fine Chemicals;PEG Product
• Mol File: 57103-68-1.mol
• Article Data: 12

Chemical Properties

• Melting Point: 205-207℃
• Boiling Point: 835.8°Cat760mmHg
• Flash Point: 459.3°C
• Appearance: /
• Density: 1.34g/cm³
• Vapor Pressure: 1.24E-29mmHg at 25°C
• Refractive Index: 1.607
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 9.89±0.70(Predicted)
• CAS DataBase Reference: Maytansine, O3-de2-(acetylmethylamino)-1-oxopropyl-(CAS DataBase Reference)
• NIST Chemistry Reference: Maytansine, O3-de2-(acetylmethylamino)-1-oxopropyl-(57103-68-1)
• EPA Substance Registry System: Maytansine, O3-de2-(acetylmethylamino)-1-oxopropyl-(57103-68-1)

Safety Data

• Hazardous Substances Data: 57103-68-1(Hazardous Substances Data)

Usage

Description

Maytansinol (Ansamitocin P-0) is an inhibitor of microtubule assembly that induces microtubule disassembly in vitro.

Uses

Maytansinol is used in the preparation of site-specific trastuzumab maytansinoid antibody-drug conjugates with improved therapeutic activity. References Pillow, T.H., et. al.: J. Med. Chem., 57, 7890 (2014)

Biological Activity

Maytansinol is an ansamacrolide originally isolated from P. verrucose that has antimitotic and anticancer activities. It inhibits polymerization and induces depolymerization of bovine brain tubulin with EC50 values of 12 and 43 μM, respectively. Maytansinol inhibits sea urchin egg mitosis when used at a concentration of 10 μM and decreases proliferation of KB nasopharyngeal cancer cells (EC50 = 0.19 μg/ml).

Mode of action

Maytansinol (1 b) was first obtained by Kupchan et?al. both by isolation from Putterlickia verrucose and chemical removal of the acyl group from the hydroxy group at the C3 position. It showed weaker inhibitory activity on tubulin polymerization than maytansine, thus implying that the ester moiety at the C3 position of ansamitocins, maytansine, and maytansinoids plays an important role for biological activity and cell permeability. In fact, it has just recently been found that the carbonyl oxygen atom of the ester moiety forms a strong intramolecular interaction with the hydroxy group at position 9, fixing the bioactive conformation. Maytansinol has been regarded as a valuable precursor because acylation allows the preparation of both natural and new semisynthetic maytansinoids, differing in the ester side-chain substituents (Scheme 1). The acylation reaction of maytansinol is a crucial step in the preparation of maytansinoid ADCs or nanoparticles, constituting an uprising class of targeted cancer therapeutics. A few attempts to conjugate maytansinoids to peptides by this reaction have also been made very recently. Furthermore, considering that the maytansine binding site is one of the most recently identified and least explored on tubulin, acylation of maytansinol may serve for the preparation of useful molecular probes to better understand the structure-activity relationships of maytansinoids or to identify new maytansine-site ligands.Structure of maytansine (1 a), maytansinol (1 b), and the generic acylation reaction of maytansinol.

InChI:InChI=1/C28H37ClN2O8/c1-15-8-7-9-22(37-6)28(35)14-20(38-26(34)30-28)16(2)25-27(3,39-25)21(32)13-23(33)31(4)18-11-17(10-15)12-19(36-5)24(18)29/h7-9,11-12,16,20-22,25,32,35H,10,13-14H2,1-6H3,(H,30,34)/b9-7+,15-8-

Synthetic route

ansamitocin P-3 (66584-72-3, 93221-27-3) → maytansinol (57103-68-1)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran at -20℃; for 2h;
With lithium (hydro)trimethoxyaluminate
With lithium (hydro)trimethoxyaluminate
With lithium (hydro)trimethoxyaluminate In tetrahydrofuran at -40℃;
With lithium (hydro)trimethoxyaluminate In tetrahydrofuran at -40℃; for 1.5h; Inert atmosphere;

maytanbutine (38997-10-3, 70774-06-0) → maytansinol (57103-68-1)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran at -23℃; for 3h;

(-)-maytansinol (75340-68-0, 93221-25-1, 109764-37-6) → maytansinol (57103-68-1)

Conditions	Yield
hydrolysis;

4-deoxymaytansinol (75340-67-9) → maytansinol (57103-68-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 0.1 percent p-toluenesulfonic acid / 0.5 h / 25 °C 2: 87 percent / tert-butyl hydroperoxide, oxyvanadium(IV) bis(acetylacetonate), 2,6-lutidine / benzene; toluene / 3.5 h / 25 °C 3: hydrolysis View Scheme

(3E,5E,14E)-(7R,8S,12S,13S,16S)-21-Chloro-16-hydroxy-7,8,22-trimethoxy-3,13,15,19-tetramethyl-11-oxa-9,19-diaza-tricyclo[18.3.1.18,12]pentacosa-1(24),3,5,14,20,22-hexaene-10,18-dione (75349-70-1) → maytansinol (57103-68-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 87 percent / tert-butyl hydroperoxide, oxyvanadium(IV) bis(acetylacetonate), 2,6-lutidine / benzene; toluene / 3.5 h / 25 °C 2: hydrolysis View Scheme

C36H56ClNO5S2Si (75340-66-8) → maytansinol (57103-68-1)

Conditions

Yield

Multi-step reaction with 6 steps 1: 1.) pyridine, 2.) aq. ammonium hydroxide / 1.) 27 deg C, 20 min, 2.) tert-butyl alcohol, 27 deg C, 2 h 2: mercuric chloride, aq. calcium carbonate / acetonitrile / 12 h / 25 °C 3: 83 percent / aq. HF / acetonitrile / 0.75 h / 0 °C 4: 0.1 percent p-toluenesulfonic acid / 0.5 h / 25 °C 5: 87 percent / tert-butyl hydroperoxide, oxyvanadium(IV) bis(acetylacetonate), 2,6-lutidine / benzene; toluene / 3.5 h / 25 °C 6: hydrolysis View Scheme

3-O-(tert-butyldimethylsilyl)-4,5-deoxymaytansinol (75349-69-8) → maytansinol (57103-68-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 83 percent / aq. HF / acetonitrile / 0.75 h / 0 °C 2: 0.1 percent p-toluenesulfonic acid / 0.5 h / 25 °C 3: 87 percent / tert-butyl hydroperoxide, oxyvanadium(IV) bis(acetylacetonate), 2,6-lutidine / benzene; toluene / 3.5 h / 25 °C 4: hydrolysis View Scheme

C37H57ClN2O6S2Si (75349-68-7) → maytansinol (57103-68-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: mercuric chloride, aq. calcium carbonate / acetonitrile / 12 h / 25 °C 2: 83 percent / aq. HF / acetonitrile / 0.75 h / 0 °C 3: 0.1 percent p-toluenesulfonic acid / 0.5 h / 25 °C 4: 87 percent / tert-butyl hydroperoxide, oxyvanadium(IV) bis(acetylacetonate), 2,6-lutidine / benzene; toluene / 3.5 h / 25 °C 5: hydrolysis View Scheme

C40H64ClNO6S2Si → maytansinol (57103-68-1)

Conditions

Yield

Multi-step reaction with 7 steps 1: 1.) 2-propanethiol, boron trifluoride etherate, 2.) silver nitrate, aq. 2,6-lutidine / 1.) methylene chloride, - 78 deg C, 5 min, 2.) THF, 25 deg C, 1.75 h 2: 1.) pyridine, 2.) aq. ammonium hydroxide / 1.) 27 deg C, 20 min, 2.) tert-butyl alcohol, 27 deg C, 2 h 3: mercuric chloride, aq. calcium carbonate / acetonitrile / 12 h / 25 °C 4: 83 percent / aq. HF / acetonitrile / 0.75 h / 0 °C 5: 0.1 percent p-toluenesulfonic acid / 0.5 h / 25 °C 6: 87 percent / tert-butyl hydroperoxide, oxyvanadium(IV) bis(acetylacetonate), 2,6-lutidine / benzene; toluene / 3.5 h / 25 °C 7: hydrolysis View Scheme

(E)-(3S,6S,7S)-3-(tert-Butyl-dimethyl-silanyloxy)-8-{2-[(2E,4E)-(R)-6-(4-chloro-3-methoxy-5-methylamino-phenyl)-1-methoxy-5-methyl-hexa-2,4-dienyl]-[1,3]dithian-2-yl}-7-(2-methoxy-propoxy)-4,6-dimethyl-oct-4-enoatetetrabutyl-ammonium; → maytansinol (57103-68-1)

Conditions

Yield

Multi-step reaction with 8 steps 1: 71 percent / mesitylenesulfonyl chloride, diisopropylethylamine / benzene / 28 h / 40 °C 2: 1.) 2-propanethiol, boron trifluoride etherate, 2.) silver nitrate, aq. 2,6-lutidine / 1.) methylene chloride, - 78 deg C, 5 min, 2.) THF, 25 deg C, 1.75 h 3: 1.) pyridine, 2.) aq. ammonium hydroxide / 1.) 27 deg C, 20 min, 2.) tert-butyl alcohol, 27 deg C, 2 h 4: mercuric chloride, aq. calcium carbonate / acetonitrile / 12 h / 25 °C 5: 83 percent / aq. HF / acetonitrile / 0.75 h / 0 °C 6: 0.1 percent p-toluenesulfonic acid / 0.5 h / 25 °C 7: 87 percent / tert-butyl hydroperoxide, oxyvanadium(IV) bis(acetylacetonate), 2,6-lutidine / benzene; toluene / 3.5 h / 25 °C 8: hydrolysis View Scheme

maytansinol (57103-68-1) + (L)-3,4-dimethyl-1,3-oxazolidine-2,5-dione (58311-53-8) → (14S,16S,32R,33R,2R,4S,10E,12E,14R)-86-chloro-14-hydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl methyl-L-alaninate (77668-69-0)

Conditions	Yield
With zinc trifluoromethanesulfonate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 48h; Inert atmosphere;	95%
With zinc trifluoromethanesulfonate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 48h; Inert atmosphere;
With zinc trifluoromethanesulfonate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide for 24h;

N-(9-fluorenylmethoxycarbonyl)-N-methyl-L-alanine (84000-07-7) + maytansinol (57103-68-1) → Fmoc-N-Me-D/L-Ala-maytansinol

Conditions	Yield
Stage #1: N-(9-fluorenylmethoxycarbonyl)-N-methyl-L-alanine; maytansinol With dmap; scandium tris(trifluoromethanesulfonate) In dichloromethane at -8℃; for 0.5h; Stage #2: With diisopropyl-carbodiimide at -8 - 20℃; for 0.5h;	90.5%
Stage #1: N-(9-fluorenylmethoxycarbonyl)-N-methyl-L-alanine; maytansinol With dmap; scandium tris(trifluoromethanesulfonate) In dichloromethane at -8℃; for 0.5h; Stage #2: With diisopropyl-carbodiimide at -8 - 20℃; for 0.5h;	90.5%
Stage #1: N-(9-fluorenylmethoxycarbonyl)-N-methyl-L-alanine; maytansinol With dmap; scandium tris(trifluoromethanesulfonate) In dichloromethane at -8℃; for 0.5h; Stage #2: With diisopropyl-carbodiimide In dichloromethane at -8 - 20℃; for 0.5h;	90.5%

maytansinol (57103-68-1) + (L)-3,4-dimethyl-1,3-oxazolidine-2,5-dione (58311-53-8) → maytansinol 3-(S)-α-N-methylaminopropionate

Conditions	Yield
With zinc(II) trifluoroacetate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 40h; Product distribution / selectivity;	84%
Stage #1: maytansinol; (L)-3,4-dimethyl-1,3-oxazolidine-2,5-dione With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 0.0333333 - 0.05h; Stage #2: With zinc(II) trifluoroacetate In tetrahydrofuran at 50 - 55℃; for 28h; Product distribution / selectivity;

C8H14N4O3 + maytansinol (57103-68-1) → C36H49ClN6O10

Conditions	Yield
With zinc(II) chloride; diisopropyl-carbodiimide In diethyl ether; dichloromethane at 20℃; for 2h; Inert atmosphere;	74%

C8H14N4O3 + maytansinol (57103-68-1) → C36H49ClN6O10

Conditions	Yield
Stage #1: C8H14N4O3; maytansinol With diisopropyl-carbodiimide In dichloromethane for 0.0166667h; Inert atmosphere; Stage #2: With zinc(II) chloride In diethyl ether; dichloromethane at 20℃; for 2h; Inert atmosphere;	74%

1-isocyanato-3-methoxy-4-nitrobenzene + maytansinol (57103-68-1) → maytan-3-O-carbamoyl-N-(3-methoxy-4-nitrobenzene)

Conditions	Yield
With zinc(II) chloride In diethyl ether; dichloromethane at 20℃; for 18h; Sealed tube; Inert atmosphere;	67%

2-chloro-1-isocyanato-4-nitro-benzene (40397-95-3) + maytansinol (57103-68-1) → maytan-3-O-carbamoyl-N-(2-chloro-4-nitrobenzene)

Conditions	Yield
With zinc(II) chloride In diethyl ether; dichloromethane at 20 - 50℃; Sealed tube; Inert atmosphere;	58%

N-(9-fluorenylmethoxycarbonyl)-N-methyl-L-alanine (84000-07-7) + maytansinol (57103-68-1) → Fmoc-N-Me-D-Ala-maytansinol (1452404-53-3) + Fmoc-N-Me-L-Ala-maytansinol (1452404-52-2)

Conditions	Yield
Stage #1: N-(9-fluorenylmethoxycarbonyl)-N-methyl-L-alanine; maytansinol With dmap; scandium tris(trifluoromethanesulfonate) In dichloromethane at -8℃; for 0.5h; Stage #2: With diisopropyl-carbodiimide In dichloromethane at -8 - 20℃;	A 43.1% B 46%
Stage #1: N-(9-fluorenylmethoxycarbonyl)-N-methyl-L-alanine; maytansinol With dmap; scandium tris(trifluoromethanesulfonate) In dichloromethane at -8℃; for 0.5h; Stage #2: With diisopropyl-carbodiimide In dichloromethane at -8 - 20℃; for 0.5h;	A 43.1% B 46%
Stage #1: N-(9-fluorenylmethoxycarbonyl)-N-methyl-L-alanine; maytansinol With dmap; scandium tris(trifluoromethanesulfonate) In dichloromethane at -8℃; for 0.5h; Stage #2: With diisopropyl-carbodiimide In dichloromethane at -8 - 20℃; for 0.5h;	A 43.1% B 46%
Stage #1: N-(9-fluorenylmethoxycarbonyl)-N-methyl-L-alanine; maytansinol With dmap; scandium tris(trifluoromethanesulfonate) In dichloromethane at -8℃; for 0.5h; Inert atmosphere; Stage #2: With diisopropyl-carbodiimide In dichloromethane at -8℃; for 0.5h; Inert atmosphere; Overall yield = 90.5 %; Overall yield = 0.8385 g;	A 43.1% B 46%
Multi-step reaction with 2 steps 1.1: dmap; scandium tris(trifluoromethanesulfonate) / dichloromethane / 0.5 h / -8 °C 1.2: 0.5 h / -8 - 20 °C 2.1: silica gel / dichloromethane; methanol / Resolution of racemate View Scheme

N-methyl-N-[(4-(R,S)-methyldithio)-1-oxopentyl]-L-alanine (796073-60-4) + maytansinol (57103-68-1) → N2'-deacetyl-N2'-[4-(R,S)-(methyldithio)-1-oxopentyl]maytansine (796073-70-6) + C38H54ClN3O10S2

Conditions	Yield
With dicyclohexyl-carbodiimide; zinc(II) chloride In diethyl ether; dichloromethane at 20℃; for 2h;	A 36% B 30%

N-methyl-N-[4-methyl-(4-methyldithio)-1-oxopentyl]-L-alanine (796073-57-9) + maytansinol (57103-68-1) → N2'-deacetyl-N2'-[4-methyl-4-(methyldithio)-1-oxopentyl]maytansine (796073-68-2) + N2'-deacetyl-N2'-[4-methyl-4-(methyldithio)-1-oxopentyl]-D-maytansine (902768-55-2)

Conditions	Yield
With dicyclohexyl-carbodiimide; zinc(II) chloride In diethyl ether; dichloromethane at 20℃; for 2h;	A 36% B n/a

4-Nitrophenyl isocyanate (100-28-7) + maytansinol (57103-68-1) → maytan-3-O-carbamoyl-N-(4-nitrobenzene)

Conditions	Yield
With zinc(II) chloride In diethyl ether; dichloromethane at 20℃; for 18h; Inert atmosphere; Sealed tube;	34%

N-methyl-N-[(3-methyldithio)-1-oxopropyl]-L-alanine (138148-62-6) + maytansinol (57103-68-1) → N2'-deacetyl-N2'-[3-(methyldithio)-1-oxopropyl]maytansine (138148-68-2) + N2'-deacetyl-N2'-[2-(methyldithio)-1-oxopropyl]maytansine

Conditions	Yield
With dicyclohexyl-carbodiimide; zinc(II) chloride In diethyl ether; dichloromethane at 20℃; for 2h;	A 32% B 30%

3,4-dimethyl-2-thioxo-oxazolidin-5-one + maytansinol (57103-68-1) → (14S,16S,32R,33R,2R,4S,10E,12E,14R)-86-chloro-14-hydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl methyl-L-alaninate (77668-69-0) + N-Me-D-Ala-maytansinol (77714-98-8)

Conditions	Yield
With zinc trifluoromethanesulfonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 50℃; for 4h; Glovebox; Inert atmosphere; Sealed tube;	A 21% B 20%

3,4-dimethyl-2-thioxo-oxazolidin-5-one + maytansinol (57103-68-1) → (14S,16S,32R,33R,2R,4S,10E,12E,14R)-86-chloro-14-hydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl methyl-L-alaninate (77668-69-0)

Conditions	Yield
With zinc trifluoromethanesulfonate; N-ethyl-N,N-diisopropylamine In 2-methyltetrahydrofuran; N,N-dimethyl-formamide at 20 - 50℃; for 44h; Sealed tube; Glovebox;	21%

N-((1,2-dithiolan-3-yl)pentanoyl)-N-methyl-L-alanine + maytansinol (57103-68-1) → (14S,16S,32S,33S,2R,4S,10E,12E,14R)-86-chloro-14-hydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl N-((1,2-dithiolan-3-yl)pentanoyl)-N-methyl-L-alaninate + (14S,16S,32S,33S,2R,4S,10E,12E,14R)-86-chloro-14-hydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl N-((1,2-dithiolan-3-yl)pentanoyl)-N-methyl-D-alaninate

Conditions	Yield
Stage #1: N-((1,2-dithiolan-3-yl)pentanoyl)-N-methyl-L-alanine; maytansinol With dicyclohexyl-carbodiimide In dichloromethane for 0.0166667h; Stage #2: With zinc(II) chloride In dichloromethane at 20℃; for 24h;	A 16% B 14%

N-((5-(S)-1,2-dithiolan-3-yl)pentanoyl)-N-methyl-L-alanine + maytansinol (57103-68-1) → (14S,16S,32S,33S,2R,4S,10E,12E,14R)-86-chloro-14-hydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl N-((5-(S)-1,2-dithiolan-3-yl)pentanoyl)-N-methyl-L-alaninate + (14S,16S,32S,33S,2R,4S,10E,12E,14R)-86-chloro-14-hydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl N-((5-(S)-1,2-dithiolan-3-yl)pentanoyl)-N-methyl-D-alaninate

Conditions	Yield
Stage #1: N-((5-(S)-1,2-dithiolan-3-yl)pentanoyl)-N-methyl-L-alanine; maytansinol With dicyclohexyl-carbodiimide In dichloromethane for 0.0166667h; Stage #2: With zinc(II) chloride In dichloromethane at 20℃; for 24h;	A 12% B 14.2%

N-((5-(R)-1,2-dithiolan-3-yl)pentanoyl)-N-methyl-L-alanine + maytansinol (57103-68-1) → (14S,16S,32S,33S,2R,4S,10E,12E,14R)-86-chloro-14-hydroxy- 85,14-dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl N-((5-(R)-1,2-dithiolan-3-yl)pentanoyl)-N-methyl-D-alaninate + (14S,16S,32S,33S,2R,4S,10E,12E,14R)-86-chloro-14-hydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl N-((5-(R)-1,2-dithiolan-3-yl)pentanoyl)-N-methyl-L-alaninate

Conditions	Yield
Stage #1: N-((5-(R)-1,2-dithiolan-3-yl)pentanoyl)-N-methyl-L-alanine; maytansinol With dicyclohexyl-carbodiimide In dichloromethane for 0.0166667h; Stage #2: With zinc(II) chloride In dichloromethane at 20℃; for 24h;	A 10.6% B 10.7%
Stage #1: N-((5-(R)-1,2-dithiolan-3-yl)pentanoyl)-N-methyl-L-alanine; maytansinol With dicyclohexyl-carbodiimide In dichloromethane for 0.0166667h; Stage #2: With zinc(II) chloride In dichloromethane at 20℃; for 24h;	A 10.7% B 10.6%

bromoacetic anhydride (13094-51-4) + maytansinol (57103-68-1) → (3E,5E,7R,84S)-12c-bromoacetoxy-14-chloro-10t,11c-epoxy-84-hydroxy-15,7r-dimethoxy-3,9c,11t,15-tetramethyl-(84r'H,86c'H)-15-aza-1(1,3)-benzena-8(4,6)-[1,3]oxazinana-cyclopentadecaphane-3,5-diene-82,14-dione (57103-71-6)

Conditions	Yield
With pyridine at 45℃; for 18h;

acetic anhydride (108-24-7) + maytansinol (57103-68-1) → ansamitocin P1 (57103-69-2)

Conditions	Yield
With pyridine at 53℃; for 18h;
With pyridine for 18h; Ambient temperature;

crotonic anhydride (623-68-7) + maytansinol (57103-68-1) → (3E,5E,7R,84S)-12c-but-2t-enoyloxy-14-chloro-10t,11c-epoxy-84-hydroxy-15,7r-dimethoxy-3,9c,11t,15-tetramethyl-(84r'H,86c'H)-15-aza-1(1,3)-benzena-8(4,6)-[1,3]oxazinana-cyclopentadecaphane-3,5-diene-82,14-dione (57103-72-7)

Conditions	Yield
With pyridine at 65℃; for 20h;

propionic acid anhydride (123-62-6) + maytansinol (57103-68-1) → (3E,5E,7R,84S)-14-chloro-10t,11c-epoxy-84-hydroxy-15,7r-dimethoxy-3,9c,11t,15-tetramethyl-12c-propionyloxy-(84r'H,86c'H)-15-aza-1(1,3)-benzena-8(4,6)-[1,3]oxazinana-cyclopentadecaphane-3,5-diene-82,14-dione (57103-70-5)

Conditions	Yield
With pyridine at 45℃; for 72h;

maytansinol (57103-68-1) + trifluoroacetic anhydride (407-25-0) → (3E,5E,7R,84S)-14-chloro-10t,11c-epoxy-84-hydroxy-15,7r-dimethoxy-3,9c,11t,15-tetramethyl-12c-trifluoroacetoxy-(84r'H,86c'H)-15-aza-1(1,3)-benzena-8(4,6)-[1,3]oxazinana-cyclopentadecaphane-3,5-diene-82,14-dione (57103-73-8)

Conditions	Yield
With trifluoroacetic acid In dichloromethane at -10℃; for 0.25h;

N-methyl-N-[(2-methyldithio)-1-oxoethyl]-L-alanine + maytansinol (57103-68-1) → N2'-deacetyl-N2'-[2-(methyldithio)-1-oxoethyl]maytansine + N2'-deacetyl-N2'-[2-(methyldithio)-1-oxoethyl]maytansine

Conditions	Yield
With dicyclohexyl-carbodiimide; zinc(II) chloride In diethyl ether; dichloromethane at 20℃; for 2h;

N-methyl-N-[(3-methyldithio)-1-oxobutyl]-L-alanine (138148-63-7) + maytansinol (57103-68-1) → N2'-deacetyl-N2'-[3-(methyldithio)-1-oxobutyl]maytansine + C37H52ClN3O10S2

Conditions	Yield
With dicyclohexyl-carbodiimide; zinc(II) chloride In diethyl ether; dichloromethane at 20℃; for 2h;

N-methyl-N-[(4-(S)-methyldithio)-1-oxopentyl]-S-alanine (796073-78-4) + maytansinol (57103-68-1) → N2'-deacetyl-N2'-[4-(S)-(methyldithio)-1-oxopentyl]maytansine + N2'-deacetyl-N2'-[4-(S)-(methyldithio)-1-oxopentyl]-D-maytansine

Conditions	Yield
With dicyclohexyl-carbodiimide; zinc(II) chloride In diethyl ether; dichloromethane at 20℃; for 2h;

N-methyl-N-[(4-(R)-methyldithio)-1-oxopentyl]-S-alanine (796073-74-0) + maytansinol (57103-68-1) → N2'-deacetyl-N2'-[4-(R)-(methyldithio)-1-oxopentyl]maytansine + C38H54ClN3O10S2

Conditions	Yield
With dicyclohexyl-carbodiimide; zinc(II) chloride In diethyl ether; dichloromethane at 20℃; for 2h;

N-methyl-N-(3-phenyldithio-propanoyl)-L-alanine (382599-34-0) + maytansinol (57103-68-1) → N2'-deacetyl-N2'-[3-(phenyldithio)-1-oxopropyl]maytansine + C41H52ClN3O10S2

Conditions	Yield
With dicyclohexyl-carbodiimide; zinc(II) chloride In diethyl ether; dichloromethane at 20℃; for 2h;

Upstream product

• 66584-72-3 ansamitocin P-3 
• 66584-72-3 ansamitocin P-3 
• 75340-68-0 (-)-maytansinol 
• 75340-67-9 4-deoxymaytansinol 
• 75349-70-1 (3E,5E,14E)-(7R,8S,12S,13S,16S)-21-Chloro-16-hydroxy-7,8,22-trimethoxy-3,13,15,19-tetramethyl-11-oxa-9,19-diaza-tricyclo[18.3.1.1^8,12]pentacosa-1⁽²⁴⁾,3,5,14,20,22-hexaene-10,18-dione 
• 75340-66-8 C₃₆H₅₆ClNO₅S₂Si 
• 75349-69-8 3-O-(tert-butyldimethylsilyl)-4,5-deoxymaytansinol 
• 75349-68-7 C₃₇H₅₇ClN₂O₆S₂Si 
• 75340-68-0 3-epimaytansinol 9-methyl ether 
• 78760-20-0 3-maytansinone 9-methyl ether 
• 57103-68-1 (-)-maytansinol 
• 75340-68-0 maytansinol 9-methyl ether 
• 75448-82-7 C₂₈H₃₅ClN₂O₈ 
• 82599-00-6 (2-Chloro-5-iodomethyl-3-methoxy-phenyl)-methyl-carbamic acid methyl ester 

Downstream Products

• 57103-69-2 Maytanacin 
• 72887-71-9 maytansinol 3-benzoate 
• 66547-09-9 maytansinol 3-butyrate 
• 72887-68-4 maytansinol 3-cylcohexanecarboxylate 
• 66584-72-3 3-epimaytansinol 3-isobutyrate 
• 72887-70-8 3-epimaytansinol 3-phenylacetate 
• 57103-68-1 3-epimaytansinol 
• 66584-72-3 ansamitocin P-3 
• 57103-69-2 maytanacine 
• 796073-68-2 N^2'-deacetyl-N^2'-[4-methyl-4-(methyldithio)-1-oxopentyl]maytansine 
• 139504-50-0 N^2'-deacetyl-N^2'-(3-mercapto-1-oxopropyl)maytansine 
• 902768-55-2 N^2'-deacetyl-N^2'-[4-methyl-4-(methyldithio)-1-oxopentyl]-D-maytansine 
• 77679-96-0 maytansinol 3-D-mandelate 

Relevant articles and documents

Structural requirements for antileukemic activity among the naturally occurring and semisynthetic maytansinoids.

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.

A highly potent maytansinoid analogue and its use as a cytotoxic therapeutic agent in gold nanoparticles for the treatment of hepatocellular carcinoma

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.

Uses of immunoconjugates targeting CD138

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.

MAYTANSINOID ANALOGS AS ANTITUMOR AGENTS

Ansamycin analogs, including maytansinoid analogs, and their use in treating cell proliferative diseases and conditions, and in particular, for use as antitumor agents.