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Hoshinolactam, A new antitrypanosomal lactam

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Abstract Image
Tropical diseases caused by parasitic protozoa are a threat to human health, mainly in developing countries. Trypanosomiasis (Chagas disease and sleeping sickness) and leishmaniasis, inter alia, are classified as neglected tropical diseases, and over 400 million people are at risk of contracting these diseases.

In addition, a parasite of the Trypanosoma genus, Trypanosoma brucei brucei, is the causative agent of Nagana disease in wild and domestic animals, and this disease is a major obstacle to the economic development of affected rural areas.

Although some therapeutic agents for these diseases exist, they have limitations, such as serious side effects and the emergence of drug resistance. Thus, new and more effective antiprotozoal medicines are needed

Marine natural products have recently been considered to be good sources for drug leads. In particular, secondary metabolites produced by marine cyanobacteria have unique structures and versatile biological activities, and some of these compounds show antiprotozoal activities. For example, coibacin A isolated from cf. Oscillatoria sp. exhibited potent antileishmanial activity, and viridamide A isolated from Oscillatoria nigro-viridis showed antileishmanial and antitrypanosomal activities.

constituents of marine cyanobacteria and reported an antitrypanosomal cyclodepsipeptide, janadolide.

The marine cyanobacterium was collected at the coast near Hoshino, Okinawa.

Image result for OKINAWA

Image result for OKINAWA

Okinawa
沖縄市
Uchinaa
City
Okinawa City downtown.jpg
Flag of Okinawa
Flag

EARLIER MERCK TEAM HAD REPORTED

CAS 159153-15-8
MF C20 H33 N O5
MW 367.48
2-Pyrrolidinone, 3,4-dihydroxy-5-(hydroxymethyl)-3-[3-(2-nonylcyclopropyl)-1-oxo-2-propenyl]-, [3S-[3α,3[E(1S*,2S*)],4β,5α]]-
Image result for AntitrypanosomalImage result for Antitrypanosomal
Antitrypanosomal
Image result for marine cyanobacterium
Marine cyanobacterium
Image result for human fetal lung fibroblast MRC-5 cells
Human fetal lung fibroblast MRC-5 cells
Majusculoic acid.png
Majusculoic acid
Image result for malyngamide A.
Malyngamide A.

PAPER

http://pubs.acs.org/doi/suppl/10.1021/acs.orglett.7b00047

Recently, we isolated a new antitrypanosomal lactam, hoshinolactam (1), from a marine cyanobacterium.Structurally, 1 contains a cyclopropane ring and a γ-lactam ring. So far, some metabolites possessing either a cyclopropane ring or a γ-lactam ring have been discovered from marine cyanobacteria, such as majusculoic acid and malyngamide A. To the best of our knowledge, on the other hand, hoshinolactam (1) is the first compound discovered in marine cyanobacteria that possesses both of these ring systems. In addition, we clarified that 1 exhibited potent antitrypanosomal activity without cytotoxicity against human fetal lung fibroblast MRC-5 cells. Here, we report the isolation, structure elucidation, first total synthesis, and preliminary biological characterization of hoshinolactam (1).

Isolation and Total Synthesis of Hoshinolactam, an Antitrypanosomal Lactam from a Marine Cyanobacterium

Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan
Research Center for Tropical Diseases, Kitasato Institute for Life Sciences, and §Graduate School of Infection Control Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan
Org. Lett., Article ASAP
DOI: 10.1021/acs.orglett.7b00047

Abstract Image

In the search for new antiprotozoal substances, hoshinolactam, an antitrypanosomal lactam, was isolated from a marine cyanobacterium. The gross structure was elucidated by spectroscopic analyses, and the absolute configuration was determined by the first total synthesis. Hoshinolactam showed potent antitrypanosomal activity with an IC50 value of 3.9 nM without cytotoxicity against human fetal lung fibroblast MRC-5 cells (IC50 > 25 μM).

Table 1. 1H and 13C NMR Data for 1 in C6D6
unit position δCa δHb (J in Hz)
HIMP 1 177.8, C
2 44.1, CH 2.51, dq (5.2, 7.6)
3 80.8, CH 4.94, dd (4.6, 5.2)
4 57.3, CH 3.49, ddd (4.6, 4.7, 9.4)
5a 44.6, CH2 1.21, m
5b 1.36, m
6 25.0, CH 1.61, m
7 21.7, CH3 0.74, d (6.2)
8 23.2, CH3 0.76, d (6.3)
9 15.0, CH3 1.33, d (7.6)
NH 7.65, s
PCPA 1 166.0, C
2 117.4, CH 5.88, d (15.5)
3 155.0, CH 6.59, dd (10.3, 15.5)
4 22.4, CH 0.91, m
5 23.3, CH 0.59, m
6 35.7, CH2 0.96, m
7 22.5, CH2 1.20, tq (7.1, 7.3)
8 14.0, CH3 0.78, t (7.3)
9a 16.1, CH2 0.35, ddd (4.5, 6.0, 8.2)
9b 0.42, ddd (4.5, 4.5, 8.8)
aMeasured at 100 MHz.
bMeasured at 400 MHz.
Positive HRESIMS data (m/z 308.2228, calcd for C18H30NO3 [M + H]+ 308.2225). Table 1 shows the NMR data for 1.
An analysis of the 1H NMR spectrum indicated the presence of four methyl groups (δH 0.74, 0.76, 0.78 and 1.33), four protons of the cyclopropane ring (δH 0.35, 0.42, 0.59 and 0.91), and two olefinic protons (δH 5.88 and 6.59).
The 13C NMR and HMQC spectra revealed the existence of two carbonyl groups (δC 166.0 and 177.8) and two sp2 methines (δC 117.4 and 155.0).
Examination of the COSY and HMBC spectra established the presence of two fragments derived from 4-hydroxy-5-isobutyl-3-methylpyrrolidin-2-one (HIMP) and 3-(2-propylcyclopropyl) acrylic acid (PCPA), respectively. The configuration of the C-2–C-3 olefinic bond in the PCPA was determined to be trans on the basis of the coupling constant (3JH2–H3 = 15.5 Hz). The connectivity of the two partial structures was determined from the HMBC correlation (H-3 of HIMP/C-1 of PCPA).
1H, 13C, COSY, HMQC, HMBC, and NOESY NMR spectra in C6D6 and 1H and 13C NMR spectra in CD3OD for hoshinolactam (1)
1H, 13C, COSY, HMQC, HMBC, and NOESY NMR spectra in C6D6

1H and 13C NMR spectra in CD3OD

1H NMR PREDICT

13 C NMR PREDICT

Image result for OKINAWAImage result for OKINAWA

OKINAWA

///////////Hoshinolactam

CC(C)C[C@@H]2NC(=O)[C@H](C)C2OC(=O)/C=C/[C@H]1C[C@@H]1CCC

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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