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Many natural products from marine sources are endowed with promising anti hypertensive activity, thus representing invaluable leads in the plans for drug discovery. In this context, organic synthesis plays a decisive role in confirming (or revising) the chemical structures of the natural compounds allowing also access to suitable amounts of the target (and its analogs) for structure activity relationship (SAR) investigations. In this overview, we focus on the total and partial synthesis of marine metabolites and their related compounds discussing the retro synthetic analysis of the strategies adopted used in treatment of hypertension.

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n s dighe et al

N S Digheet al

______________________________________________________________________________

Journal of Chemical and Pharmaceutical Research2009, 1 (1): 54-61

Recent synthesis of marine natural products with

antihypertensive activity: An overview

Nachiket S Dighe*, Shashikant R Pattan, Deepak S Musmade, Prerana A Chavan,

Snehalata K Tambe, Manjusha S Sanap, Vinayak M Gaware

Department of Pharmaceutical Chemistry, Pravara Rural College of Pharmacy,

Pravaranagar, M.S., India

______________________________________________________________________________

Abstract

Many natural products from marine sources are endowed with promising anti hypertensive

activity, thus representing invaluable leads in the plans for drug discovery. In this context,

organic synthesis plays a decisive role in confirming (or revising) the chemical structures of the

natural compounds allowing also access to suitable amounts of the target (and its analogs) for

structure activity relationship (SAR) investigations. In this overview, we focus on the total and

partial synthesis of marine metabolites and their related compounds discussing the retro synthetic

analysis of the strategies adopted used in treatment of hypertension.

Keywords: Marine, Anti hypertensive Activity, Synthesis of Marine metabolites.

______________________________________________________________________________

Introduction

The antihypertensives are a class of drugs that are used to treat hypertension (high blood

pressure).[1] Evidence suggests that reduction of the blood pressure by 5–6 mmHg can decrease

the risk of stroke by 40%, of coronary heart disease by 15–20%, and reduce the likelihood of

dementia, heart failure, and mortality from cardiovascular disease. There are many classes of

antihypertensives, which lower blood pressure by different means; among the most important

and most widely used are the thiazide diuretics, the ACE inhibitors, the calcium channel

blockers, the beta blockers, and the angiotensin II receptor antagonists or ARBs.Which type of

medication to use initially for hypertension has been the subject of several large studies and

resulting national guidelines. The fundamental goal of treatment should be the prevention of the

important endpoints of hypertension, such as heart attack, stroke and heart failure. The several

classes of antihypertensives differ in side effect profiles, ability to prevent endpoints, and cost.

The choice of more expensive agents, where cheaper ones would be equally effective, may have

negative impacts on national healthcare budgets.[2] As of 2009, the best available evidence

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n s dighe et al favors the thiazide diuretics

N S Digheet al

______________________________________________________________________________

favors the thiazide diuretics as the first-line treatment of choice for high blood pressure when

drugs are necessary.[3]

Available agents

1.1 Diuretics

1.2 Adrenergic receptor antagonists

1.3 Adrenergic receptor agonists

1.4 Calcium channel blockers

1.5 ACE inhibitors

1.6 Angiotensin II receptor antagonists

1.7 Aldosterone antagonists

1.8 Vasodilators

1.9 Centrally acting adrenergic drugs

The choice between the drugs is to a large degree determined by the characteristics of the patient

being prescribed for, the drugs' side-effects, and cost. For example, asthmatics have been

reported to have worsening symptoms when using beta blockers. Most drugs have other uses;

sometimes the presence of other symptoms can warrant the use of one particular antihypertensive

(such as beta blockers in case of tremor and nervousness, and alpha blockers in case of benign

prostatic hyperplasia). The JNC 7 report outlines compelling reasons to choose one drug over the

others for certain individual patients.[4]

Marine organisms, particularly sponge invertebrates and associated bacteria, are a prolific source

of novel biologically active compounds with unusual, and often complex, structures. The harsh

environment that marine sponges inhabit, together with their lack of physical defenses, requires

that these organisms develop chemical deterrents to aid their survival. As a result, many of their

associated secondary metabolites exhibit exceptional levels of biological activity, often

combined with unique modes of action. However, the potential therapeutic utility of marine-

derived natural products is hampered not only by the limited supply, but often also by their

incomplete stereo chemical assignment. In both these respects, total synthesis can provide a

powerful solution.

1. Synthesis of Xestoquinone [5]

A strategy for synthesis of the furan-fused tetracyclic system of Xestoquinone was explored

through a model study. Using 3-butyn-1-ol as a starting material, 5-iodo-1-methoxymethoxy

pentyne was prepared in 5 steps. Reaction of ethyl 2-phenylpropanoate with gave ethyl 7-

methoxymethoxy-2-methyl-2-phenyl-5-heptynoate in 88% yield, and then methyl 9-oxo-4-

methyl-4-phenyl-2,7-nonadiynoate ,the key intermediate, was synthesized in 6 steps from the

ester 6. Intramolecular cycloaddition reaction of afforded isobenzofuran in 5% yield, which was

converted to the tetracyclic structure in the presence of Lewis acid.

Journal of Chemical and Pharmaceutical Research2009, 1 (1): 54-61

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n s dighe et al 1

N S Digheet al

______________________________________________________________________________

Journal of Chemical and Pharmaceutical Research2009, 1 (1): 54-61

H

O

(i-Pr)2NEt

I2,PPh3,Imidazole

OMOM

OMOM

I

CH2Cl2,20h

n-BuLi,THF

CH3

CH3

CH3

LDA,THF,(i-Pr)2NH

OMOM

OMOM

CO2Et

CO2Et

DIABH,toluene,2h

CHO

CBr3

PPh3,CH2Cl2,3h

CH3

CH3

CH3

n-BuLi

OMOM

OMOM

OMOM

Br

n-BuLi,THF

H

H

Br

H

CO2CH3

PPTS,t-BuOH

CH3

CH3

OH

1,1 Dess Martin Reaction

H

O

O

H

H

H3CO

toluene,110

CO2CH3

CO2CH3

O

CBr3,CH2Cl2

O

O

O

O

O

O

Scheme: Synthesis of Xestoquinone

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n s dighe et al 2 synthesis of halenaquinone 5

N S Digheet al

______________________________________________________________________________

2. Synthesis of Halenaquinone [5]

Journal of Chemical and Pharmaceutical Research2009, 1 (1): 54-61

H

O

(i-Pr)2NEt

I2,PPh3,Imidazole

OMOM

OMOM

I

CH2Cl2,20h

n-BuLi,THF

CH3

CH3

CH3

LDA,THF,(i-Pr)2NH

OMOM

OMOM

CO2Et

CO2Et

DIABH,toluene,2h

CHO

CBr3

PPh3,CH2Cl2,3h

CH3

CH3

CH3

n-BuLi

OMOM

OMOM

OMOM

Br

n-BuLi,THF

H

H

Br

H

CO2CH3

PPTS,t-BuOH

CH3

CH3

OH

1,1 Dess Martin Reaction

H

O

O

H

H

H3CO

toluene,110

CO2CH3

CO2CH3

O

CBr3,CH2Cl2

O

O

O

O

O

O

O

Scheme: Synthesis of Halenaquinone

3. Synthesis of N1-Alkylisoguanosines [6]

N1-Alkylisoguanosines were synthesized. Their chemical and physical properties and biological

activities were compared with those of marine natural product, doridosine. N1-

Alkylisoguanosines appears to exist in the structure of N1-alkyl-6-amino-2-oxo-β-D-

ribofuranosyl purine, in water, dioxane, acetonitrile and dimethyl sulfoxide solution. The

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n s dighe et al biological activity

N S Digheet al

______________________________________________________________________________

biological activity of N1-ethylisoguanosines was run on guinea pig atria and the same type of

activity of doridosine was found, but ca. half of that from doidosine (N1-methylisoguanosines).

O

Ac2O/Pyridine

Journal of Chemical and Pharmaceutical Research2009, 1 (1): 54-61

NC

N

NC

RNCO/DMF

N

N

H2

N

N

NH

Et3N

POCl3/Et3N

N

N

H2

N

H2

N

Rib(OAc)

(RCN)2

Rib(OAc)

Rib

OH

NH4OH,MeOH

NH2

R

N

N

N

O

N

O

H

O

OH

OH

Scheme: Synthesis of N1-Alkylisoguanosines

4. Synthesis of 2'-Deoxyisoguanosine 5'-Triphosphate [7]

N(Bu)2

CH

N

NH2

N

N

N

NH2

OH

N

OH

N

CH2

N

N

N

CH2

N

O

O

N

OH

O

O

N

CH2

N

NH2

O

OH

OH

N(Bu)2

OH

OH

CH

N(Bu)2

N(Bu)2

N

OH

OH

CH

CH

N

N

N

N

TMSO

N

N

N

N

CH2

N

OH

N

TMSO

O

O

N

CH2

N

N

CH2

ODPC

N

O

ODPC

O

TMSO

TMSO

OH

OH

TMSO

TMSO

Scheme: Synthesis of 2'-Deoxyisoguanosine 5'-Triphosphate

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n s dighe et al 5 synthesis of 2 deoxy

N S Digheet al

______________________________________________________________________________

5. Synthesis of 2'-Deoxy-5-methylisocytidine 5'-Triphosphate [7]

Journal of Chemical and Pharmaceutical Research2009, 1 (1): 54-61

N(Bu)2

CH

N

NH2

N

N

N

NH2

OH

N

OH

N

CH2

N

N

N

CH2

N

O

O

N

OH

O

O

N

CH2

N

NH2

O

OH

OH

N(Bu)2

OH

OH

CH

N(Bu)2

N(Bu)2

N

OH

OH

CH

CH

N

N

N

N

TMSO

N

N

N

N

CH2

N

OH

N

TMSO

O

O

N

CH2

N

N

CH2

ODPC

N

O

ODPC

O

TMSO

TMSO

OH

OH

TMSO

TMSO

Scheme: Synthesis of 2'-Deoxy-5-methylisocytidine 5'-Triphosphate

6. Synthesis of Araguspongine C [8]

N

O

H

H

O

H

O

OH

N

Araguspongine C

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n s dighe et al 7 synthesis of pyridoacridines 9

N S Digheet al

______________________________________________________________________________

7. Synthesis of pyridoacridines [9]

Journal of Chemical and Pharmaceutical Research2009, 1 (1): 54-61

O

O

H2

N

O

NH

N

X

X

O

N

X

O

NH

R

O

Me2N

Scheme: Synthesis of pyridoacridines

8. Synthesis of Deoxyamphimedine [10]

H3

C

N

N

O

N

O

O

H2

N

O

NH

N

X

X

O

N

X

O

NH

R

O

Me2N

Scheme: Synthesis of Deoxyamphimedine

Conclusion

Natural products traditionally have played a pivotal role in drug discovery and in particular the

uniqueness of marine metabolite core structures makes these compounds of interest in the

development of pharmaceutical agents, in particular the anti hypertensive here discussed. In

these studies, chemical synthesis still represents a route of choice showing its potential to

confirm or revise the chemical structures of the natural products and to allow the access to

related compounds for structure activity relationship investigations. The actual interest in this

field is confirmed by several reports on the synthesis of marine natural products with anti

hypertensive activity. This overview focuses on the main aspects of such reports strongly relying

on the corresponding retro synthetic sequences.

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n s dighe et al refrences

N S Digheet al

______________________________________________________________________________

Refrences

Journal of Chemical and Pharmaceutical Research2009, 1 (1): 54-61

1.K D Tripathi, Essentials of Medical Pharmacology, 5th Edition, Jaypee Publication, 2003,

503-518.

2.MR Nelson, JJ McNeil, A Peeters. Med J Aust, 1994-1998, 174 (11): 565–8.

3.JM Wright, VM Musini. Cochrane Database Syst RevJul 2009,8 (3): CD001841.

4.AV Chobanian et al. the JNC 7 report". 2003, JAMA 289: 2560–72.

5.Mug Ahn Chan and Bum Woo Ho. Journal of the Korean Chemical Society, 2003, Vol.

47, No. 4.123-126.

6.In Kwon Youn and Yong Hae Kim, Korean Biochem Journal, 1981,.44,124-136.

7.Simona C. Jurczyka, Janos T. Kodrab, Jeong-Ho Parkb, Steven A. Bennerb, Thomas R.

Battersbya. Helvetica Chimica Acta,1999 Vol. 82;23-28.

8.VP Limna Mol, TV Raveendran & PS Parameswaran. Int. Biodeterior. Biodegrad.2009;

63(1); 67-72.

9.Juan M. Cuerva, Diego J. Cárdenas and Antonio M. Echavarren. Chem. Commun., 1999,

1721–1722.

10.Kathryn M. Marshall, Cynthia D. Andjelic, Deniz Tasdemir, Gisela P. Concepción,Chris

M. Ireland and Louis R. Barrows. Mar. Drugs; 2009, 7, 196-209.

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