Marinopyrrole A (also known as Maritoclax) is a natural product and a selective antagonist of Mcl-1 with anticancer activity. Mcl-1 is a member of the anti-apoptotic Bcl-2 family of proteins, which also includes the well-validated drug targets Bcl-2, Bcl-X(L), and Mcl-1. While ABT-737 and its orally active analog ABT-263 are the most potent and specific inhibitors to date that bind Bcl-2 and Bcl-X(L) with high affinity but have a much lower affinity for Mcl-1, they are not very effective as single agents in certain cancer types due to elevated levels of Mcl-1. However, by binding to and targeting Mcl-1 for proteasomal degradation, Marinopyrrole A can overcome ABT-737 resistance. Maritoclax has an IC50 of 10.1 μM, which is sufficient to interfere with the interaction between Bim and Mcl-1. Maritoclax's pro-apoptotic activity is connected to the way mariopyrrole A induces Mcl-1 degradation through the proteasome system. ABT-737's effectiveness against hematologic malignancies, such as K562, Raji, and multidrug-resistant HL60/VCR, is significantly increased by Marinopyrrole A by 60- to 2000-fold at 1-2 μM, selectively killing Mcl-1-dependent leukemia cells but not Bcl-2 or Bcl-XL-dependent leukemia cells.

Physicochemical Properties

Molecular Formula	C22H12CL4N2O4
Molecular Weight	510.15
Exact Mass	507.955
CAS #	1227962-62-0
Related CAS #	1227962-62-0
PubChem CID	24797083
Appearance	Light yellow to yellow solid
Density	1.6±0.1 g/cm3
Boiling Point	732.4±60.0 °C at 760 mmHg
Flash Point	396.7±32.9 °C
Vapour Pressure	0.0±2.5 mmHg at 25°C
Index of Refraction	1.708
LogP	6.91
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	5
Heavy Atom Count	32
Complexity	715
Defined Atom Stereocenter Count	0
SMILES	OC1=CC=CC=C1C(C2=C(N3C(C(C4=CC=CC=C4O)=O)=CC(Cl)=C3Cl)C(Cl)=C(Cl)N2)=O
InChi Key	QYPJBTMRYKRTFG-UHFFFAOYSA-N
InChi Code	InChI=1S/C22H12Cl4N2O4/c23-12-9-13(19(31)10-5-1-3-7-14(10)29)28(22(12)26)18-16(24)21(25)27-17(18)20(32)11-6-2-4-8-15(11)30/h1-9,27,29-30H
Chemical Name	[4,5-dichloro-1-[4,5-dichloro-2-(2-hydroxybenzoyl)-1H-pyrrol-3-yl]pyrrol-2-yl]-(2-hydroxyphenyl)methanone
Synonyms	Maritoclax; (±)-Marinopyrrole; (-)-Marinopyrrole A; Marinopyrrole A
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	Mcl-1 (IC50 = 10.1 μM)
ln Vitro	Maritoclax induces Mcl-1 degradation via the proteasome system, which is associated with the pro-apoptotic activity of maritoclax. Maritoclax selectively kills Mcl-1-dependent leukemia cells but not Bcl-2 or Bcl-XL-dependent leukemia cells, and at concentrations of 1-2 M, it significantly increases the effectiveness of ABT-737 against hematologic malignancies like K562, Raji, and multidrug-resistant HL60/VCR. Maritoclax has an IC50 value of 10.1 M and inhibits the binding of biotin-labeled Bim-BH3 peptide to GST-Mcl-1 in a dose-dependent manner. However, at concentrations up to 80 M, it does not inhibit the binding of Bim-BH3 peptide to GST-Bcl-XL. By causing the protein Mcl-1 to degrade, maritoclax activates caspase-3. Treatment with maritoclax markedly reduces the half-life of Mcl-1 to ∼0.5 h as compared with nearly 3 h in control cells. Maritoclax appears to have no impact on Mcl-1's (Ser159/Thr163) phosphorylation, indicating that it may cause Mcl-1 degradation independent of phosphorylation[1]. Against clinically important hospital- and community-acquired MRSA strains, Marinopyrrole A exhibits potent concentration-dependent bactericidal activity. (at >20× MIC)[2] Marinopyrrole A exhibits only minor toxicity to mammalian cell lines. Maritoclax sensitivity depends on the type of cell. In HeLa, HEK293, or MEF cells, it is useless. Maritoclax is not a substrate for drug efflux caused by p-gp[3].
ln Vivo	Maritoclax administration at 20 mg/kg/d intraperitoneally causes significant U937 tumor shrinkage as well as a 36% tumor remission rate in athymic nude mice, without apparent toxicity to healthy tissue or circulating blood cells[3].
Cell Assay	For 12 hours, DMSO, 2 μM maritoclax alone or in combination with 1 M MG132 are applied to K562 cells expressing Mcl-1-IRES-BimEL. Protease inhibitors are added to 1% Chaps buffer, which is used to lyse cells (1% Chaps, 150 mM NaCl, 10 mM Hepes, pH 7.4). 350 g of protein-containing cell lysates are incubated with either control pre-immune serum or 4 μl of rabbit anti-Mcl-1 antiserum in 250 μl of the same lysis buffer at 4 °C for an entire night on a rotator. Adding 20 l of protein A-Sepharose beads for 3 hours at 4 °C, followed by 30 seconds of centrifugation at 6,000 rpm, is how immunoprecipitates are collected.
Animal Protocol	Female athymic nude (NCI Athymic NCr-nu/nu 01B74) mice 20 mg/kg i.p.
References	[1]. Discovery of marinopyrrole A (maritoclax) as a selective Mcl-1 antagonist that overcomes ABT-737 resistance by binding to and targeting Mcl-1 for proteasomal degradation. J Biol Chem. 2012 Mar 23;287(13):10224-35. [2]. Pharmacological properties of the marine natural product marinopyrrole A against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2011 Jul;55(7):3305-12. [3]. The selectivity of Marinopyrrole A to induce apoptosis in MCL1high BCL2low expressing myeloma cells is related to its ability to impair protein translation. Br J Haematol. 2016 Aug 14. [4]. Purported Mcl-1 inhibitor marinopyrrole A fails to show selective cytotoxicity for Mcl-1-dependent cell lines. Cell Death Dis. 2013 Oct 24;4:e880.
Additional Infomation	(-)-marinopyrrole A is a member of the class of pyrroles that is 1'H-1,3'-bipyrrole substituted by four chloro groups at positions 4, 4', 5 and 5' and two 2-hydroxybenzoyl moieties at positions 2 and 2'. It is isolated from Streptomyces sp.CNQ-418 and exhibits cytotoxic and antibacterial activities. It has a role as an antimicrobial agent, an antibacterial agent, an antineoplastic agent, a marine metabolite and a bacterial metabolite. It is a member of pyrroles, an organochlorine compound, a member of phenols and an aromatic ketone.

Solubility Data

Solubility (In Vitro)

DMSO: ~100 mg/mL (~196.0 mM) Water: <1 mg/mL Ethanol: ~45 mg/mL (~88.2 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.90 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (4.90 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (4.90 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.9602 mL	9.8010 mL	19.6021 mL
	5 mM	0.3920 mL	1.9602 mL	3.9204 mL
	10 mM	0.1960 mL	0.9801 mL	1.9602 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.